Spirocyclic ror-gamma modulators

ABSTRACT

Described herein are retinoic acid related-related orphan nuclear receptor (ROR) modulators and methods of utilizing ROR-gamma modulators in the treatment of diseases, disorders or conditions. Also described herein are pharmaceutical compositions containing such compounds.

CROSS-REFERENCE

This application is a continuation of U.S. application Ser. No.16/979,833, filed Sep. 10, 2020, which is a National Phase ofInternational Application No. PCT/US2019/021671, filed Mar. 11, 2019,which claims benefit of U.S. Provisional Application No. 62/641,949,filed on Mar. 12, 2018, which are herein incorporated by reference intheir entirety.

BACKGROUND OF THE INVENTION

The retinoic acid related orphan nuclear receptors (RORs) have threemembers: RORα, RORβ and RORγ. RORβ expression is mostly restricted tothe brain and retina, while RORα and RORγ expressions are widespread.RORγ also has a shorter isoform, RORγt, which is mostly expressed in theimmune system.

RORγt is essential for the development of secondary lymphoid tissues, inparticular lymph nodes and Peyer's patches. Recent studies identified acritical role for RORγt in lineage specification of uncommitted CD4+ Thelper cells into Th17 cells as well as the development of Tc17(cytotoxic) T cells. Th17 response has been implicated in a myriad ofautoimmune diseases such as psoriasis, inflammatory bowel disease,arthritis and multiple scoliosis. Inhibition of Th17 and Tc17 responsehas also been shown to a mechanism for cancer cells to evade anti-tumorimmunity in several experimental tumor models. These findings implicateboth RORγ agonists and inverse agonists as potential therapeutics for avariety of diseases.

SUMMARY OF THE INVENTION

In one aspect, provided herein are compounds having the Formula (I), ora pharmaceutically acceptable salt, solvate, or stereoisomer thereof:

wherein:

is phenyl, or a 5-membered or 6-membered heteroaryl ring;

is phenyl, or a 5-membered or 6-membered heteroaryl ring;Z is —(C(R⁶)(R⁷))_(t)—;

-   R¹ and R² are selected from (i) and (ii):-   (i) R¹ and R², together with the carbon atom to which they are    attached, form a 4-, 5-, or 6-membered heterocyclyl ring wherein the    4-, 5-, or 6-membered heterocyclyl ring is optionally substituted    with 1 to 4 R^(3a) groups; and-   (ii) R¹ is hydrogen and R² is —S(O)₂R¹⁰, —C₁-C₆alkyl-S(O)₂R¹⁰,    —N(R¹¹)S(O)₂R¹⁰, or —C₁-C₆alkyl-N(R¹¹)S(O)₂R¹⁰;-   each R³ is independently selected from halo and C₁-C₆alkyl;-   each R^(3a) is independently selected from C₁-C₆alkyl,    C₁-C₆haloalkyl, C₂-C₉heteroaryl, (C₂-C₉heteroaryl)-C₁-C₆alkylene-,    oxo, —S(O)₂R¹⁰, —C(O)R¹⁰, —C(O)OR¹¹, and —C(O)N(R¹¹)₂, wherein    C₂-C₉heteroaryl and (C₂-C₉heteroaryl)-C₁-C₆alkylene- are optionally    substituted with 1 to 3 groups independently selected from halo,    C₁-C₆alkyl, C₁-C₆haloalkyl, and hydroxyl;-   each R⁴ and each R⁵ are each independently selected from halo,    cyano, —OH, C₁-C₆alkyl, C₁-C₆alkenyl, C₁-C₆haloalkyl, C₁-C₆alkoxy,    C₃-C₈cycloalkyl, —N(R⁹)₂, —C(O)R⁸, —C(O)OR⁹, —C(O)N(R⁹)₂,    —N(R⁹)C(O)R⁸, —N(R⁹)SO₂R⁸, —SO₂R⁸, and —SO₂N(R⁸)₂;-   each R⁶ and each R⁷ are each independently hydrogen, halo, or    C₁-C₆alkyl;-   each R⁸ is independently C₁-C₆alkyl or C₁-C₆haloalkyl;-   each R⁹ is independently hydrogen, C₁-C₆alkyl, or C₁-C₆haloalkyl;-   each R¹⁰ is independently C₁-C₆alkyl, C₁-C₆haloalkyl,    C₁-C₆alkyl-O—C₁-C₆alkyl-, C₃-C₈cycloalkyl, C₂-C₉heterocyclyl,    phenyl, (phenyl)-C₁-C₆alkylene-, C₂-C₉heteroaryl, or    (C₂-C₉heteroaryl)-C₁-C₆alkylene-, wherein the C₃-C₈cycloalkyl,    C₂-C₉heterocyclyl, phenyl, (phenyl)-C₁-C₆alkylene-, C₂-C₉heteroaryl,    or (C₂-C₉heteroaryl)-C₁-C₆alkylene- is optionally substituted with 1    to 3 groups selected from halo, C₁-C₆alkyl, C₁-C₆haloalkyl, and    hydroxyl;-   each R¹¹ is independently hydrogen, C₁-C₆alkyl, or C₁-C₆haloalkyl;-   m is 1, 2, or 3;-   n is 1, 2, or 3;-   k is 0, 1, 2, 3, or 4;-   p is 0, 1, 2, 3, or 4;-   q is 0, 1, 2, 3 or 4; and-   t is 0, 1, 2, or 3.

In some embodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein

is phenyl or a 6-membered heteroaryl ring. In some embodiments is acompound of Formula (I), or a pharmaceutically acceptable salt, solvate,or stereoisomer thereof, wherein

is phenyl. In some embodiments is a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein

is a 6-membered heteroaryl ring. In some embodiments is a compound ofFormula (I), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein

is pyridyl. In some embodiments is a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein

is phenyl or a 6-membered heteroaryl ring. In some embodiments is acompound of Formula (I), or a pharmaceutically acceptable salt, solvate,or stereoisomer thereof, wherein

is phenyl. In some embodiments is a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein

is a 6-membered heteroaryl ring. In some embodiments is a compound ofFormula (I), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein

is pyridyl. In some embodiments is a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein R¹ and R², together with the carbon atom to which they areattached, form a 4-, 5-, or 6-membered heterocyclyl ring, wherein the4-, 5-, or 6-membered heterocyclyl ring is optionally substituted with 1to 4 R^(3a) groups. In some embodiments is a compound of Formula (I), ora pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein R¹ and R², together with the carbon atom to which they areattached, form a 4-, 5-, or 6-membered heterocyclyl ring, wherein the4-, 5-, or 6-membered heterocyclyl ring is optionally substituted with 1to 2 R^(3a) groups. In some embodiments is a compound of Formula (I), ora pharmaceutically acceptable salt, solvate, or stereoisomer thereof,having the Formula (II):

wherein X is —O—, —NH—, —N(R^(3a))—, —S—, —S(O)—, or —S(O)₂—; a is 1 or2; and b is 1 or 2. In some embodiments is a compound of Formula (II),or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein a is 1, b is 1, m is 2, and n is 2. In some embodiments is acompound of Formula (II), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein a is 1, b is 2, m is 1, and nis 2. In some embodiments is a compound of Formula (II), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein a is 1, b is 1, m is 1, and n is 2. In some embodiments is acompound of Formula (II), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein a is 2, b is 2, m is 1, and nis 1. In some embodiments is a compound of Formula (II), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein a is 2, b is 1, m is 1, and n is 1. In some embodiments is acompound of Formula (II), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein a is 1, b is 1, m is 1, and nis 1. In some embodiments is a compound of Formula (II), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,having the Formula (IIa):

In some embodiments is a compound of Formula (I), (II), or (IIa), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein R^(3a) is —S(O)₂R¹⁰, —C(O)R¹⁰, or —C(O)OR¹¹. In some embodimentsis a compound of Formula (I), (II), or (IIa), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein R^(3a) is—S(O)₂R¹⁰. In some embodiments is a compound of Formula (I), (II), or(IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, wherein R¹⁰ is C₁-C₆alkyl or C₃-C₈cycloalkyl. In someembodiments is a compound of Formula (I), (II), or (IIa), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein R¹⁰ is C₁-C₆alkyl. In some embodiments is a compound of Formula(I), (II), or (IIa), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein R^(3a) is —S(O)₂CH₃. In some embodimentsis a compound of Formula (I), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein R¹ is hydrogen and R² is—S(O)₂R¹⁰, —C₁-C₆alkyl-S(O)₂R¹⁰, —N(R¹¹)S(O)₂R¹⁰, or—C₁-C₆alkyl-N(R¹¹)S(O)₂R¹⁰. In some embodiments is a compound of Formula(I), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, wherein R² is —S(O)₂R¹⁰, —CH₂S(O)₂R¹⁰, —N(R¹¹)S(O)₂R¹⁰, or—CH₂N(R¹¹)S(O)₂R¹⁰. In some embodiments is a compound of Formula (I), ora pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein R¹⁰ is C₁-C₆alkyl. In some embodiments is a compound of Formula(I), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, wherein R² is —S(O)₂CH₃, —CH₂S(O)₂CH₃, —CH₂N(H)S(O)₂CH₃, or—CH₂N(CH₃)S(O)₂CH₃. In some embodiments is a compound of Formula (I), ora pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein m is 1 and n is 1. In some embodiments is a compound of Formula(I), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, wherein m is 2 and n is 1. In some embodiments is a compound ofFormula (I), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein m is 2 and n is 2. In some embodiments isa compound of Formula (I), (II), or (IIa), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein each R⁶ andeach R⁷ are hydrogen. In some embodiments is a compound of Formula (I),(II), or (IIa), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein t is 1, 2, or 3. In some embodiments is acompound of Formula (I), (II), or (IIa), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein t is 1. Insome embodiments is a compound of Formula (I), (II), or (IIa), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein p is 0, 1, 2, or 3. In some embodiments is a compound of Formula(I), (II), or (IIa), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein each R⁴ is independently halo, C₁-C₆alkyl,C₁-C₆alkenyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, or C₃-C₈cycloalkyl. In someembodiments is a compound of Formula (I), (II), or (IIa), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein each R⁴ is independently halo, C₁-C₆alkyl, or C₃-C₈cycloalkyl.In some embodiments is a compound of Formula (I), (II), or (IIa), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein p is 1. In some embodiments is a compound of Formula (I), (II),or (IIa), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein p is 2. In some embodiments is a compoundof Formula (I), (II), or (IIa), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein p is 3. In some embodiments isa compound of Formula (I), (II), or (IIa), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein p is 0. Insome embodiments is a compound of Formula (I), (II), or (IIa), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein q is 0, 1, or 2. In some embodiments is a compound of Formula(I), (II), or (IIa), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein each R⁵ is independently halo, cyano,C₁-C₆alkyl, C₁-C₆haloalkyl, or C₁-C₆alkoxy. In some embodiments is acompound of Formula (I), (II), or (IIa), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein each R⁵ isindependently halo or C₁-C₆alkyl. In some embodiments is a compound ofFormula (I), (II), or (IIa), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein q is 1. In some embodiments isa compound of Formula (I), (II), or (IIa), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein q is 2. Insome embodiments is a compound of Formula (I), (II), or (IIa), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein q is 0. In some embodiments is a compound of Formula (I), (II),or (IIa), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein k is 0.

In another aspect is a pharmaceutical composition comprising a compoundof Formula (I), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, and a pharmaceutically acceptable carrier. In someembodiments is a pharmaceutical composition comprising a compound ofFormula (II), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, and a pharmaceutically acceptable carrier. In someembodiments is a pharmaceutical composition comprising a compound ofFormula (IIa), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, and a pharmaceutically acceptable carrier.

In another aspect is a method of treating a disease, disorder orcondition in an individual in need thereof comprising administering tothe individual a therapeutically effective amount of a compound ofFormula (I), (II), or (IIa), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein the disease, disorder orcondition is selected from psoriasis, psoriatic arthritis, uveitis,ulcerative colitis, asthma, allergic rhinitis, chronic obstructivepulmonary disease (COPD), atopic dermatitis, vitiligo, vesiculobullousdermatosis, rheumatoid arthritis, ankylosing spondylitis, reactivearthritis, arthritis associated with inflammatory bowel disease,juvenile rheumatoid arthritis, Crohn's disease, inflammatory boweldisease, lupus, lupus nephritis, multiple sclerosis, axialspodyloarthritides, hidraenitis suppurativa, Sjögren's syndrome,regional enteritis, Tolosa-Hunt syndrome, undifferentiated connectivetissue disease, obesity, obesity-induced insulin resistance,atherosclerosis, and type II diabetes.

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference to the same extent asif each individual publication, patent, or patent application wasspecifically and individually indicated to be incorporated by reference.

DETAILED DESCRIPTION OF THE INVENTION Definitions

In the context of this disclosure, a number of terms shall be utilized.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood to which the claimedsubject matter belongs. In the event that there are a plurality ofdefinitions for terms herein, those in this section prevail. Allpatents, patent applications, publications and published nucleotide andamino acid sequences (e.g., sequences available in GenBank or otherdatabases) referred to herein are incorporated by reference. Wherereference is made to a URL or other such identifier or address, it isunderstood that such identifiers can change and particular informationon the internet can come and go, but equivalent information can be foundby searching the internet. Reference thereto evidences the availabilityand public dissemination of such information.

It is to be understood that the foregoing general description and thefollowing detailed description are exemplary and explanatory only andare not restrictive of any subject matter claimed. In this application,the use of the singular includes the plural unless specifically statedotherwise. It must be noted that, as used in the specification and theappended claims, the singular forms “a,” “an” and “the” include pluralreferents unless the context clearly dictates otherwise. In thisapplication, the use of “or” means “and/or” unless stated otherwise.Furthermore, use of the term “including” as well as other forms, such as“include”, “includes,” and “included,” is not limiting.

The section headings used herein are for organizational purposes onlyand are not to be construed as limiting the subject matter described.

Definition of standard chemistry terms may be found in reference works,including but not limited to, Carey and Sundberg “Advanced OrganicChemistry 4^(th) Ed.” Vols. A (2000) and B (2001), Plenum Press, NewYork. Unless otherwise indicated, conventional methods of massspectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinantDNA techniques and pharmacology.

Unless specific definitions are provided, the nomenclature employed inconnection with, and the laboratory procedures and techniques of,analytical chemistry, synthetic organic chemistry, and medicinal andpharmaceutical chemistry described herein are those recognized in thefield. Standard techniques can be used for chemical syntheses, chemicalanalyses, pharmaceutical preparation, formulation, and delivery, andtreatment of patients. Standard techniques can be used for recombinantDNA, oligonucleotide synthesis, and tissue culture and transformation(e.g., electroporation, lipofection). Reactions and purificationtechniques can be performed e.g., using kits of manufacturer'sspecifications or as commonly accomplished in the art or as describedherein.

The foregoing techniques and procedures can be generally performed ofconventional methods and as described in various general and morespecific references that are cited and discussed throughout the presentspecification.

It is to be understood that the methods and compositions describedherein are not limited to the particular methodology, protocols, celllines, constructs, and reagents described herein and as such may vary.It is also to be understood that the terminology used herein is for thepurpose of describing particular embodiments only, and is not intendedto limit the scope of the methods, compounds, compositions describedherein.

As used herein, C₁-C_(x) includes C₁-C₂, C₁-C₃ . . . C₁-C_(x). C₁-C_(x)refers to the number of carbon atoms that make up the moiety to which itdesignates (excluding optional substituents).

An “alkyl” group refers to an aliphatic hydrocarbon group. The alkylgroups may or may not include units of unsaturation. The alkyl moietymay be a “saturated alkyl” group, which means that it does not containany units of unsaturation (i.e. a carbon-carbon double bond or acarbon-carbon triple bond). The alkyl group may also be an “unsaturatedalkyl” moiety, which means that it contains at least one unit ofunsaturation. The alkyl moiety, whether saturated or unsaturated, may bebranched, straight chain, or cyclic.

The “alkyl” group may have 1 to 6 carbon atoms (whenever it appearsherein, a numerical range such as “1 to 6” refers to each integer in thegiven range; e.g., “1 to 6 carbon atoms” means that the alkyl group mayconsist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up toand including 6 carbon atoms, although the present definition alsocovers the occurrence of the term “alkyl” where no numerical range isdesignated). The alkyl group of the compounds described herein may bedesignated as “C₁-C₆alkyl” or similar designations. By way of exampleonly, “C₁-C₆alkyl” indicates that there are one to six carbon atoms inthe alkyl chain, i.e., the alkyl chain is selected from the groupconsisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl,sec-butyl, t-butyl, n-pentyl, iso-pentyl, neo-pentyl, hexyl, propen-3-yl(allyl), cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl,cyclohexylmethyl. Alkyl groups can be substituted or unsubstituted.Depending on the structure, an alkyl group can be a monoradical or adiradical (i.e., an alkylene group).

“Alkylene” and “alkylene chain” as used herein and unless otherwiseindicated, refer to a straight or branched divalent hydrocarbon chainconsisting solely of carbon and hydrogen, containing no unsaturation andhaving from one to eight or one to six carbon atoms, examples of whichinclude methylene, ethylene, propylene, n-butylene and the like. Thealkylene chain may be attached to the rest of the molecule through thereplacement of any two hydrogen atoms within the chain.

An “alkoxy” refers to a “—O-alkyl” group, where alkyl is as definedherein.

The term “alkenyl” refers to a type of alkyl group in which the firsttwo atoms of the alkyl group form a double bond that is not part of anaromatic group. That is, an alkenyl group begins with the atoms—C(R)═CR₂, wherein R refers to the remaining portions of the alkenylgroup, which may be the same or different. Non-limiting examples of analkenyl group include —CH═CH₂, —C(CH₃)═CH₂, —CH═CHCH₃, —CH═C(CH₃)₂ and—C(CH₃)═CHCH₃. The alkenyl moiety may be branched, straight chain, orcyclic (in which case, it would also be known as a “cycloalkenyl”group). Alkenyl groups may have 2 to 6 carbons. Alkenyl groups can besubstituted or unsubstituted. Depending on the structure, an alkenylgroup can be a monoradical or a diradical (i.e., an alkenylene group).

“Alkenylene” or “alkenylene chain” as used herein and unless otherwiseindicated, refers to a straight or branched chain unsaturated divalentgroup consisting solely of carbon and hydrogen atoms, having from two toeight carbon atoms, wherein the unsaturation is present only as doublebonds and wherein the double bond can exist between any two carbon atomsin the chain, examples of which include ethenylene, prop-1-enylene,but-2-enylene and the like. The alkenylene chain may be attached to therest of the molecule through the replacement of any two hydrogen atomswithin the chain.

The term “alkynyl” refers to a type of alkyl group in which the firsttwo atoms of the alkyl group form a triple bond. That is, an alkynylgroup begins with the atoms —C≡C—R, wherein R refers to the remainingportions of the alkynyl group. Non-limiting examples of an alkynyl groupinclude —C≡CH, —C≡CCH₃, —C≡CCH₂CH₃ and —C≡CCH₂CH₂CH₃. The “R” portion ofthe alkynyl moiety may be branched, straight chain, or cyclic. Analkynyl group can have 2 to 6 carbons. Alkynyl groups can be substitutedor unsubstituted. Depending on the structure, an alkynyl group can be amonoradical or a diradical (i.e., an alkynylene group).

“Alkynylene” or “alkynylene chain” as used herein and unless otherwiseindicated, refers to a straight or branched chain unsaturated divalentgroup consisting solely of carbon and hydrogen atoms, having from two toeight carbon atoms, wherein the unsaturation is present only as triplebonds and wherein the triple bond can exist between any two carbon atomsin the chain, examples of which include ethynylene, prop-1-ynylene,but-2-ynylene, pent-1-ynylene, pent-3-ynylene and the like. Thealkynylene chain may be attached to the rest of the molecule through thereplacement of any two hydrogen atoms within the chain.

“Amino” refers to a —NH₂ group.

The term “alkylamine” or “alkylamino” refers to the —N(alkyl)_(x)H_(y)group, where alkyl is as defined herein and x and y are selected fromthe group x=1, y=1 and x=2, y=0. When x=2, the alkyl groups, takentogether with the nitrogen to which they are attached, can optionallyform a cyclic ring system. “Dialkylamino” refers to a —N(alkyl)₂ group,where alkyl is as defined herein.

“Aralkyl” as used herein and unless otherwise indicated, refers to amonovalent alkyl group substituted with aryl. In certain embodiments,both alkyl and aryl may be optionally substituted with one or moresubstituents.

The term “aromatic” refers to a planar ring having a delocalizedπ-electron system containing 4n+2 π electrons, where n is an integer.Aromatic rings can be formed from five, six, seven, eight, nine, or morethan nine atoms. Aromatics can be optionally substituted. The term“aromatic” includes both aryl groups (e.g., phenyl, naphthalenyl) andheteroaryl groups (e.g., pyridinyl, quinolinyl). “Aryl” as used hereinand unless otherwise indicated, refers to a group of carbocylic ringsystem, including monocyclic, bicyclic, tricyclic, tetracyclic C₆-C₁₈ring systems, wherein at least one of the rings is aromatic. The arylmay be fully aromatic, examples of which are phenyl, naphthyl,anthracenyl, acenaphthylenyl, azulenyl, fluorenyl, indenyl and pyrenyl.The aryl may also contain an aromatic ring in combination with anon-aromatic ring, examples of which are acenaphthene, indene, andfluorene.

“Carboxy” refers to —CO₂H. In some embodiments, carboxy moieties may bereplaced with a “carboxylic acid bioisostere”, which refers to afunctional group or moiety that exhibits similar physical and/orchemical properties as a carboxylic acid moiety. A carboxylic acidbioisostere has similar biological properties to that of a carboxylicacid group. A compound with a carboxylic acid moiety can have thecarboxylic acid moiety exchanged with a carboxylic acid bioisostere andhave similar physical and/or biological properties when compared to thecarboxylic acid-containing compound. For example, in one embodiment, acarboxylic acid bioisostere would ionize at physiological pH to roughlythe same extent as a carboxylic acid group. Examples of bioisosteres ofa carboxylic acid include, but are not limited to,

and the like.

The term “cycloalkyl” refers to a monocyclic or polycyclic non-aromaticradical, wherein each of the atoms forming the ring (i.e. skeletalatoms) is a carbon atom. Cycloalkyls may be saturated, or partiallyunsaturated. Cycloalkyls may be fused with an aromatic ring (in whichcase the cycloalkyl is bonded through a non-aromatic ring carbon atom).Cycloalkyl groups include groups having from 3 to 10 ring atoms.

“Cycloalkylalkyl” as used herein and unless otherwise indicated, refersto a monovalent alkyl group substituted with cycloalkyl. In certainembodiments, both alkyl and cycloalkyl may be optionally substitutedwith one or more substituents.

“Deuterium” as used herein and unless otherwise indicated, refers to theheavy isotope of hydrogen represented by the symbol D or ²H. As usedherein, when a particular position in a compound is designated as havingdeuterium, it is understood that the compound is an isotopicallyenriched compound and the abundance of deuterium at that position in thecompound is substantially greater than its natural abundance of 0.0156%.

“Deuterated” as applied to a chemical group and unless otherwiseindicated, refers to a chemical group that is isotopically enriched withdeuterium in an amount substantially greater than its natural abundance.

“Heteroaralkyl” as used herein and unless otherwise indicated, refers toa monovalent alkyl group substituted with heteroaryl. In certainembodiments, both alkyl and heteroaryl may be optionally substitutedwith one or more substituents.

“Heteroaryl” as used herein and unless otherwise indicated, refers to a5- to 15-membered monocyclic aromatic ring or a multicyclic aromaticring system wherein the ring or at least one ring of the multicyclicsystem contains one to five heteroatoms each independently selected fromO, S, or N, with the remaining ring atoms being carbon atoms. Each ringof a heteroaryl group can contain up to two O atoms, up to two S atoms,and/or up to four N atoms, provided that the total number of heteroatomsin each ring is four or less and each ring contains at least one carbonatom.

Examples of such heteroaryl groups include, but are not limited to,furanyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl,thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl,tetrazolyl, pyrimidinyl, pyridinyl, pyridazinyl, pyrazinyl,benzimidazolyl, benzoisoxazolyl, benzopyranyl, benzothiadiazolyl,benzothiazolyl, pyridopyridyl, pyrrolopyridyl, quinolinyl, quinoxalinyl,quinazolinyl, naphthridinyl, 1,5-naphthyridinyl, 1,6-naphthyridinyl,thieno[3,2-b]pyridinyl, thieno[2,3-b]pyridinyl,1H-pyrazolo[4,3-b]pyridinyl, 1H-pyrrolo[2,3-b]pyridinyl,5H-pyrrolo[2,3-b]pyrazinyl, 1H-imidazo[4,5-b]pyrazinyl,1H-pyrazolo[3,4-b]pyridinyl, thiadiazolopyrimidyl, and thienopyridyl.

“Heterocyclyl”, as used herein and unless otherwise indicated, refers toa 3- to 15-membered monocyclic non-aromatic ring or a multicyclic ringsystem that contains at least one non-aromatic ring, wherein the ring orat least one ring contains one to five heteroatoms each independentlyselected from O, S, or N; and the remaining ring atoms being carbonatoms. In certain embodiments, the heterocyclyl is a monocyclic,bicyclic, tricyclic, or tetracyclic ring system, which may include afused or bridged ring system, and in which the nitrogen or sulfur atomsmay be optionally substituted with an oxo group or additionally with asecond oxo group or an imino group, the nitrogen atoms may be optionallyquaternized or substituted, and some rings may be partially or fullysaturated, or aromatic. In certain embodiments, the heterocyclyl ismonocyclic, which may include a fused or bridged ring system, and inwhich the nitrogen or sulfur atoms may be optionally substituted with anoxo group or additionally with a second oxo group or an imino group, thenitrogen atoms may be optionally quaternized or substituted with, andsome rings may be partially or fully saturated, or aromatic. Theheterocyclyl may be attached to the main structure at any heteroatom orcarbon atom which results in the creation of a stable compound. Theheterocyclyl, when substituted, may be substituted at the carbon atom orthe heteroatom. Exemplary heterocylic radicals include, but are notlimited to homopiperazinyl, morpholinyl, piperidinyl, piperazinyl,pyranyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, ethyleneoxide, oxetanyl, azetidinyl, quinuclidinyl, octahydroquinolizinyl,decahydroquinolizinyl, azabicyclo[3.2.1]octanyl,azabicyclo[2.2.2]octanyl, 6,7,8,9-tetrahydro-5H-pyrazino[2,3-b]indolyl.

“Heterocyclylalkyl” as used herein and unless otherwise indicated,refers to a monovalent alkyl group substituted with heterocyclyl. Incertain embodiments, both alkyl and heterocyclyl may be optionallysubstituted with one or more substituents.

The term “halo” or, alternatively, “halogen” means fluoro, chloro, bromoand iodo.

The term “haloalkyl” refers to an alkyl group that is substituted withone or more halogens.

The halogens may the same or they may be different. Non-limitingexamples of haloalkyls include —CH₂Cl, —CF₃, —CHF₂, —CH₂CF₃, —CF₂CF₃,and the like.

The terms “fluoroalkyl” and “fluoroalkoxy” include alkyl and alkoxygroups, respectively, that are substituted with one or more fluorineatoms. Non-limiting examples of fluoroalkyls include —CF₃, —CHF₂, —CH₂F,—CH₂CF₃, —CF₂CF₃, —CF₂CF₂CF₃, —CF(CH₃)₃, and the like. Non-limitingexamples of fluoroalkoxy groups, include —OCF₃, —OCHF₂, —OCH₂F,—OCH₂CF₃, —OCF₂CF₃, —OCF₂CF₂CF₃, —OCF(CH₃)₂, and the like.

“Imino” as used herein and unless otherwise indicated, refers to thegroup ═NH or ═NR attached to a carbon or sulfur atom.

The term “bond” or “single bond” refers to a chemical bond between twoatoms, or two moieties when the atoms joined by the bond are consideredto be part of larger substructure.

The term “moiety” refers to a specific segment or functional group of amolecule. Chemical moieties are often recognized chemical entitiesembedded in or appended to a molecule.

As used herein, the substituent “R” appearing by itself and without anumber designation refers to a substituent selected from among fromalkyl, haloalkyl, alkenyl, cycloalkyl, aryl, heteroaryl (bonded througha ring carbon), and heterocyclyl.

The term “optionally substituted” or “substituted” means that thereferenced group may be substituted with one or more additional group(s)individually and independently selected from alkyl, cycloalkyl, aryl,heteroaryl, heterocyclyl, —OH, alkoxy, aryloxy, alkylthio, arylthio,alkylsulfoxide, arylsulfoxide, alkylsulfone, arylsulfone, —CN, alkyne,C₁-C₆alkylalkyne, halo, acyl, acyloxy, —CO₂H, —CO₂-alkyl, nitro,haloalkyl, fluoroalkyl, and amino, including mono- and di-substitutedamino groups (e.g. —NH₂, —NHR, —N(R)₂), and the protected derivativesthereof. By way of example, an optional substituents may be L^(s)R^(s),wherein each L^(s) is independently selected from a bond, —O—, —C(═O)—,—S—, —S(═O)—, —S(═O)₂—, —NH—, —NHC(O)—, —C(O)NH—, S(═O)₂NH—, —NHS(═O)₂,—OC(O)NH—, —NHC(O)O—, —(C₁-C₆alkyl)-, or —(C₂-C₆alkenyl)-; and eachR^(s) is independently selected from among H, (C₁-C₆alkyl),(C₃-C₈cycloalkyl), aryl, heteroaryl, and heterocyclyl. The protectinggroups that may form the protective derivatives of the abovesubstituents are found in sources such as Greene and Wuts, above.

“Oxo” as used herein refers to the group ═O attached to a carbon orsulfur atom.

As used herein, the term “about” or “approximately” means within 20%,preferably within 10%, and more preferably within 5% of a given value orrange.

The term a “therapeutically effective amount” as used herein refers tothe amount of an RORγ modulator that, when administered to a mammal inneed, is effective to at least partially ameliorate or to at leastpartially prevent conditions related to skin aging.

As used herein, the term “expression” includes the process by whichpolynucleotides are transcribed into mRNA and translated into peptides,polypeptides, or proteins.

The term “modulate” encompasses either a decrease or an increase inactivity or expression depending on the target molecule.

The term “activator” is used in this specification to denote anymolecular species that results in activation of the indicated receptor,regardless of whether the species itself binds to the receptor or ametabolite of the species binds to the receptor when the species isadministered topically. Thus, the activator can be a ligand of thereceptor or it can be an activator that is metabolized to the ligand ofthe receptor, i.e., a metabolite that is formed in tissue and is theactual ligand.

The term “mammal” refers to a human, a non-human primate, canine,feline, bovine, ovine, porcine, murine, or other veterinary orlaboratory mammal. Those skilled in the art recognize that a therapywhich reduces the severity of a pathology in one species of mammal ispredictive of the effect of the therapy on another species of mammal.

The term “skin aging” includes conditions derived from intrinsicchronological aging (for example, deepened expression lines, reductionof skin thickness, inelasticity, and/or unblemished smooth surface),those derived from photoaging (for example, deep wrinkles, yellow andleathery surface, hardening of the skin, elastosis, roughness,dyspigmentations (age spots) and/or blotchy skin), and those derivedfrom steroid-induced skin thinning.

In the description herein, if there is any discrepancy between achemical name and chemical structure, the structure preferably controls.

RORγ Modulators

RORγ modulators contemplated for use in the compositions and methodsdescribed herein are compounds with RORγ modulator activities. The term“RORγ modulator” includes RORγ and/or RORγt agonists and inverseagonists.

In some embodiments, provided herein is a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof:

wherein:

-   is phenyl, or a 5-membered or 6-membered heteroaryl ring;-   is phenyl, or a 5-membered or 6-membered heteroaryl ring;-   Z is —(C(R⁶)(R⁷))_(t)—;-   R¹ and R² are selected from (i) and (ii):-   (i) R¹ and R², together with the carbon atom to which they are    attached, form a 4-, 5-, or 6-membered heterocyclyl ring wherein the    4-, 5-, or 6-membered heterocyclyl ring is optionally substituted    with 1 to 4 R^(3a) groups; and-   (ii) R¹ is hydrogen and R² is —S(O)₂R¹⁰, —C₁-C₆alkyl-S(O)₂R¹⁰,    —N(R¹¹)S(O)₂R¹⁰, or —C₁-C₆alkyl-N(R¹¹)S(O)₂R¹⁰;-   each R³ is independently selected from halo and C₁-C₆alkyl;-   each R^(3a) is independently selected from C₁-C₆alkyl,    C₁-C₆haloalkyl, C₂-C₉heteroaryl, (C₂-C₉heteroaryl)-C₁-C₆alkylene-,    oxo, —S(O)₂R¹⁰, —C(O)R¹⁰, —C(O)OR¹¹, and —C(O)N(R¹)₂, wherein    C₂-C₉heteroaryl and (C₂-C₉heteroaryl)-C₁-C₆alkylene- are optionally    substituted with 1 to 3 groups independently selected from halo,    C₁-C₆alkyl, C₁-C₆haloalkyl, and hydroxyl;-   each R⁴ and each R⁵ are each independently selected from halo,    cyano, —OH, C₁-C₆alkyl, C₁-C₆alkenyl, C₁-C₆haloalkyl, C₁-C₆alkoxy,    C₃-C₈cycloalkyl, —N(R⁹)₂, —C(O)R⁸, —C(O)OR⁹, —C(O)N(R⁹)₂,    —N(R⁹)C(O)R⁸, —N(R⁹)SO₂R⁸, —SO₂R⁸, and —SO₂N(R⁸)₂;-   each R⁶ and each R⁷ are each independently hydrogen, halo, or    C₁-C₆alkyl;-   each R⁸ is independently C₁-C₆alkyl or C₁-C₆haloalkyl;-   each R⁹ is independently hydrogen, C₁-C₆alkyl, or C₁-C₆haloalkyl;-   each R¹⁰ is independently C₁-C₆alkyl, C₁-C₆haloalkyl,    C₁-C₆alkyl-O—C₁-C₆alkyl-, C₃-C₈cycloalkyl, C₂-C₉heterocyclyl,    phenyl, (phenyl)-C₁-C₆alkylene-, C₂-C₉heteroaryl, or    (C₂-C₉heteroaryl)-C₁-C₆alkylene-, wherein the C₃-C₈cycloalkyl,    C₂-C₉heterocyclyl, phenyl, (phenyl)-C₁-C₆alkylene-, C₂-C₉heteroaryl,    or (C₂-C₉heteroaryl)-C₁-C₆alkylene- is optionally substituted with 1    to 3 groups selected from halo, C₁-C₆alkyl, C₁-C₆haloalkyl, and    hydroxyl;-   each R¹¹ is independently hydrogen, C₁-C₆alkyl, or C₁-C₆haloalkyl;-   m is 1, 2, or 3;-   n is 1, 2, or 3;-   k is 0, 1, 2, 3, or 4;-   p is 0, 1, 2, 3, or 4;-   q is 0, 1, 2, 3 or 4; and-   t is 0, 1, 2, or 3.

In some embodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein

and

are each independently phenyl or a 6-membered heteroaryl. In someembodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein

and

are each independently phenyl or a 5-membered heteroaryl. In someembodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein

and

are each independently selected from phenyl, pyridine, pyrimidine,pyrazine, pyridazine, pyrrole, imidazole, pyrazole, thiazole,isothiazole, oxazole, isoxazole, thiadiazole, triazole, oxadiazole,thiophene and furan. In some embodiments is a compound of Formula (I),or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein

and

are each independently selected from phenyl, pyridine, pyrimidine,pyrazine and pyridazine. In some embodiments is a compound of Formula(I), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, wherein

and

are both pyridine. In some embodiments is a compound of Formula (I), ora pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein

is selected from phenyl, pyridine, pyrimidine, pyrazine, and pyridazineand

is phenyl or pyridine. In some embodiments is a compound of Formula (I),or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein

is selected from phenyl, pyridine, pyrimidine, pyrazine, and pyridazineand

is phenyl. In some embodiments is a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein

is phenyl or pyridine and

is phenyl. In some embodiments is a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein

and

are both phenyl. In some embodiments is a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein

is pyridine and

is phenyl. In some embodiments is a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein

is phenyl and

is pyridine.

In some embodiments, provided herein is a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein each R⁶ and each R⁷ are each independently hydrogen orC₁-C₆alkyl. In some embodiments, provided herein is a compound ofFormula (I), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein each R⁶ and each R⁷ are hydrogen. In someembodiments, provided herein is a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein each R⁶ and each R⁷ are each independently C₁-C₆alkyl. In someembodiments, provided herein is a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein each R⁶ and each R⁷ are —CH₃. In some embodiments, providedherein is a compound of Formula (I), or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, wherein each R⁶ and each R⁷ areeach independently halo.

In some embodiments, provided herein is a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein t is 0. In some embodiments, provided herein is a compound ofFormula (I), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein t is 1, 2, or 3. In some embodiments,provided herein is a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein t is 1. Insome embodiments, provided herein is a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein t is 2. In some embodiments, provided herein is a compound ofFormula (I), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein t is 3.

In some embodiments, provided herein is a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein Z is —CH₂—. In some embodiments, provided herein is a compoundof Formula (I), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein Z is —CH₂CH₂—. In some embodiments,provided herein is a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein Z is—CH₂CH₂CH₂—.

In some embodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein m is 1 and nis 1. In some embodiments is a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein m is 2 and n is 1. In some embodiments is a compound of Formula(I), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, wherein m is 2 and n is 2. In some embodiments is a compound ofFormula (I), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein m is 3 and n is 1. In some embodiments isa compound of Formula (I), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein m is 3 and n is 2. In someembodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein m is 3 and nis 3.

In some embodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein R¹ and R²,together with the carbon atom to which they are attached, form a 4-, 5-,or 6-membered heterocyclyl ring, wherein the 4-, 5-, or 6-memberedheterocyclyl ring is optionally substituted with 1 to 4 R^(3a) groups.In some embodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein R¹ and R²,together with the carbon atom to which they are attached, form a4-membered heterocyclyl ring, wherein the 4-membered heterocyclyl ringis optionally substituted with 1 to 4 R^(3a) groups. In some embodimentsis a compound of Formula (I), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein R¹ and R², together with thecarbon atom to which they are attached, form a 5-membered heterocyclylring, wherein the 5-membered heterocyclyl ring is optionally substitutedwith 1 to 4 R^(3a) groups. In some embodiments is a compound of Formula(I), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, wherein R¹ and R², together with the carbon atom to which theyare attached, form a 6-membered heterocyclyl ring, wherein the6-membered heterocyclyl ring is optionally substituted with 1 to 4R^(3a) groups. In some embodiments is a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein R¹ and R², together with the carbon atom to which they areattached, form a 4-, 5-, or 6-membered heterocyclyl ring, wherein the4-, 5-, or 6-membered heterocyclyl ring is optionally substituted with 1or 2 R^(3a) groups. In some embodiments is a compound of Formula (I), ora pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein R¹ and R², together with the carbon atom to which they areattached, form a 4-membered heterocyclyl ring, wherein the 4-memberedheterocyclyl ring is optionally substituted with 1 or 2 R^(3a) groups.In some embodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein R¹ and R²,together with the carbon atom to which they are attached, form a5-membered heterocyclyl ring, wherein the 5-membered heterocyclyl ringis optionally substituted with 1 or 2 R^(3a) groups. In some embodimentsis a compound of Formula (I), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein R¹ and R², together with thecarbon atom to which they are attached, form a 6-membered heterocyclylring, wherein the 6-membered heterocyclyl ring is optionally substitutedwith 1 or 2 R³ groups. In some embodiments is a compound of Formula (I),or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein R¹ and R², together with the carbon atom to which they areattached, form a 4-, 5-, or 6-membered heterocyclyl ring, wherein the4-, 5-, or 6-membered heterocyclyl ring is optionally substituted with 1R^(3a) group. In some embodiments is a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein R¹ and R², together with the carbon atom to which they areattached, form a 4-membered heterocyclyl ring, wherein the 4-memberedheterocyclyl ring is optionally substituted with 1 R^(3a) group. In someembodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein R¹ and R²,together with the carbon atom to which they are attached, form a5-membered heterocyclyl ring, wherein the 5-membered heterocyclyl ringis optionally substituted with 1 R^(3a) group. In some embodiments is acompound of Formula (I), or a pharmaceutically acceptable salt, solvate,or stereoisomer thereof, wherein R¹ and R², together with the carbonatom to which they are attached, form a 6-membered heterocyclyl ring,wherein the 6-membered heterocyclyl ring is optionally substituted with1 R^(3a) group.

In some embodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein R¹ and R²,together with the carbon atom to which they are attached, form a 4-, 5-,or 6-membered heterocyclyl ring, wherein the 4-, 5-, or 6-memberedheterocyclyl ring is optionally substituted with 1 or 2 R^(3a) groupsand each R^(3a) is selected from C₁-C₆alkyl, C₁-C₆haloalkyl,C₂-C₉heteroaryl, (C₂-C₉heteroaryl)-C₁-C₆alkylene-, oxo, —S(O)₂R¹⁰,—C(O)R¹⁰, —C(O)OR¹¹, and —C(O)N(R¹)₂, wherein C₂-C₉heteroaryl and(C₂-C₉heteroaryl)-C₁-C₆alkylene- are optionally substituted with 1 to 3groups independently selected from halo, C₁-C₆alkyl, C₁-C₆haloalkyl, andhydroxyl. In some embodiments is a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein R¹ and R², together with the carbon atom to which they areattached, form a 4-, 5-, or 6-membered heterocyclyl ring, wherein the4-, 5-, or 6-membered heterocyclyl ring is optionally substituted with 1or 2 R^(3a) groups and each R^(3a) is selected from C₁-C₆alkyl, oxo,—S(O)₂R¹⁰, —C(O)R¹⁰, and —C(O)OR¹¹. In some embodiments is a compound ofFormula (I), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein R¹ and R², together with the carbon atomto which they are attached, form a 4-, 5-, or 6-membered heterocyclylring, wherein the 4-, 5-, or 6-membered heterocyclyl ring is optionallysubstituted with 1 or 2 R^(3a) groups and each R^(3a) is selected fromC₁-C₆alkyl, oxo, —S(O)₂R¹⁰, —C(O)R¹⁰, and —C(O)OR¹¹. In some embodimentsis a compound of Formula (I), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein R¹ and R², together with thecarbon atom to which they are attached, form a 4-membered heterocyclylring, wherein the 4-membered heterocyclyl ring is optionally substitutedwith 1 or 2 R^(3a) groups and each R^(3a) is selected from C₁-C₆alkyl,oxo, —S(O)₂R¹⁰, —C(O)R¹⁰, and —C(O)OR¹¹. In some embodiments is acompound of Formula (I), or a pharmaceutically acceptable salt, solvate,or stereoisomer thereof, wherein R¹ and R², together with the carbonatom to which they are attached, form a 5-membered heterocyclyl ring,wherein the 5-membered heterocyclyl ring is optionally substituted with1 or 2 R^(3a) groups and each R^(3a) is selected from C₁-C₆alkyl, oxo,—S(O)₂R¹⁰, —C(O)R¹⁰, and —C(O)OR¹¹. In some embodiments is a compound ofFormula (I), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein R¹ and R², together with the carbon atomto which they are attached, form a 6-membered heterocyclyl ring, whereinthe 6-membered heterocyclyl ring is optionally substituted with 1 or 2R^(3a) groups and each R^(3a) is selected from C₁-C₆alkyl, oxo,—S(O)₂R¹⁰, —C(O)R¹⁰, and —C(O)OR¹¹.

In some embodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein R¹ and R²,together with the carbon atom to which they are attached, form a 4-, 5-,or 6-membered heterocyclyl ring, wherein the 4-, 5-, or 6-memberedheterocyclyl ring is optionally substituted with 1 R^(3a) group andR^(3a) is —S(O)₂R¹⁰. In some embodiments is a compound of Formula (I),or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein R¹ and R², together with the carbon atom to which they areattached, form a 4-, 5-, or 6-membered heterocyclyl ring, wherein the4-, 5-, or 6-membered heterocyclyl ring is optionally substituted with 1R^(3a) group, R^(3a) is —S(O)₂R¹⁰, and R¹⁰ is C₁-C₆alkyl,C₁-C₆haloalkyl, C₁-C₆alkyl-O—C₁-C₆alkyl-, C₃-C₈cycloalkyl,C₂-C₉heterocyclyl, C₆-C₁₀aryl, or (C₆-C₁₀aryl)-C₁-C₆alkylene-. In someembodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein R¹ and R²,together with the carbon atom to which they are attached, form a 4-, 5-,or 6-membered heterocyclyl ring, wherein the 4-, 5-, or 6-memberedheterocyclyl ring is optionally substituted with 1 R^(3a) group, R^(3a)is —S(O)₂R¹⁰, and R¹⁰ is C₁-C₆alkyl or C₃-C₈cycloalkyl. In someembodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein R¹ and R²,together with the carbon atom to which they are attached, form a 4-, 5-,or 6-membered heterocyclyl ring, wherein the 4-, 5-, or 6-memberedheterocyclyl ring is optionally substituted with 1 R^(3a) group, R^(3a)is —S(O)₂R¹⁰, and R¹⁰ is C₁-C₆alkyl. In some embodiments is a compoundof Formula (I), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein R¹ and R², together with the carbon atomto which they are attached, form a 4-, 5-, or 6-membered heterocyclylring, wherein the 4-, 5-, or 6-membered heterocyclyl ring is optionallysubstituted with 1 R^(3a) group, R^(3a) is —S(O)₂R¹⁰, and R¹⁰ is —CH₃.In some embodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein R¹ and R²,together with the carbon atom to which they are attached, form a 4-, 5-,or 6-membered heterocyclyl ring, wherein the 4-, 5-, or 6-memberedheterocyclyl ring is optionally substituted with 1 R³ group, R³ is—S(O)₂R¹⁰, and R¹⁰ is —CH₂CH₃. In some embodiments is a compound ofFormula (I), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein R¹ and R², together with the carbon atomto which they are attached, form a 4-, 5-, or 6-membered heterocyclylring, wherein the 4-, 5-, or 6-membered heterocyclyl ring is optionallysubstituted with 1 R^(3a) group, R^(3a) is —S(O)₂R¹⁰, and R¹⁰ is—CH₂CH₂CH₃. In some embodiments is a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein R¹ and R², together with the carbon atom to which they areattached, form a 4-, 5-, or 6-membered heterocyclyl ring, wherein the4-, 5-, or 6-membered heterocyclyl ring is optionally substituted with 1R^(3a) group, R^(3a) is —S(O)₂R¹⁰, and R¹⁰ is C₃-C₈cycloalkyl. In someembodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein R¹ and R²,together with the carbon atom to which they are attached, form a 4-, 5-,or 6-membered heterocyclyl ring, wherein the 4-, 5-, or 6-memberedheterocyclyl ring is optionally substituted with 1 R^(3a) group, R^(3a)is —S(O)₂R¹⁰, and R¹⁰ is cyclopropyl.

In some embodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein R¹ and R²,together with the carbon atom to which they are attached, form a 4-, 5-,or 6-membered heterocyclyl ring, wherein the 4-, 5-, or 6-memberedheterocyclyl ring is optionally substituted with 1 R^(3a) group andR^(3a) is —C(O)R¹⁰. In some embodiments is a compound of Formula (I), ora pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein R¹ and R², together with the carbon atom to which they areattached, form a 4-, 5-, or 6-membered heterocyclyl ring, wherein the4-, 5-, or 6-membered heterocyclyl ring is optionally substituted with 1R^(3a) group, R^(3a) is —C(O)R¹⁰, and R¹⁰ is C₁-C₆alkyl, C₁-C₆haloalkyl,C₁-C₆alkyl-O—C₁-C₆alkyl-, C₃-C₈cycloalkyl, C₂-C₉heterocyclyl,C₆-C₁₀aryl, or (C₆-C₁₀aryl)-C₁-C₆alkylene-. In some embodiments is acompound of Formula (I), or a pharmaceutically acceptable salt, solvate,or stereoisomer thereof, wherein R¹ and R², together with the carbonatom to which they are attached, form a 4-, 5-, or 6-memberedheterocyclyl ring, wherein the 4-, 5-, or 6-membered heterocyclyl ringis optionally substituted with 1 R^(3a) group, R^(3a) is —C(O)R¹⁰, andR¹⁰ is C₁-C₆alkyl. In some embodiments is a compound of Formula (I), ora pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein R¹ and R², together with the carbon atom to which they areattached, form a 4-, 5-, or 6-membered heterocyclyl ring, wherein the4-, 5-, or 6-membered heterocyclyl ring is optionally substituted with 1R^(3a) group, R^(3a) is —C(O)R¹⁰, and R¹⁰ is —CH₃. In some embodimentsis a compound of Formula (I), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein R¹ and R², together with thecarbon atom to which they are attached, form a 4-, 5-, or 6-memberedheterocyclyl ring, wherein the 4-, 5-, or 6-membered heterocyclyl ringis optionally substituted with 1 R³ group, R³ is —C(O)R¹⁰, and R¹⁰ is—CH₂CH₃. In some embodiments is a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein R¹ and R², together with the carbon atom to which they areattached, form a 4-, 5-, or 6-membered heterocyclyl ring, wherein the4-, 5-, or 6-membered heterocyclyl ring is optionally substituted with 1R^(3a) group, R^(3a) is —C(O)R¹⁰, and R¹⁰ is —CH₂CH₂CH₃.

In some embodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein R¹ and R²,together with the carbon atom to which they are attached, form a 4-, 5-,or 6-membered heterocyclyl ring, wherein the 4-, 5-, or 6-memberedheterocyclyl ring is optionally substituted with 1 R^(3a) group andR^(3a) is —C(O)OR¹¹. In some embodiments is a compound of Formula (I),or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein R¹ and R², together with the carbon atom to which they areattached, form a 4-, 5-, or 6-membered heterocyclyl ring, wherein the4-, 5-, or 6-membered heterocyclyl ring is optionally substituted with 1R^(3a) group, R^(3a) is —C(O)OR¹¹, and R¹¹ is C₁-C₆alkyl. In someembodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein R¹ and R²,together with the carbon atom to which they are attached, form a 4-, 5-,or 6-membered heterocyclyl ring, wherein the 4-, 5-, or 6-memberedheterocyclyl ring is optionally substituted with 1 R^(3a) group, R^(3a)is —C(O)OR¹¹, and R¹¹ is —CH₃. In some embodiments is a compound ofFormula (I), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein R¹ and R², together with the carbon atomto which they are attached, form a 4-, 5-, or 6-membered heterocyclylring, wherein the 4-, 5-, or 6-membered heterocyclyl ring is optionallysubstituted with 1 R^(3a) group, R^(3a) is —C(O)OR¹¹, and R¹¹ is—CH₂CH₃. In some embodiments is a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein R¹ and R², together with the carbon atom to which they areattached, form a 4-, 5-, or 6-membered heterocyclyl ring, wherein the4-, 5-, or 6-membered heterocyclyl ring is optionally substituted with 1R^(3a) group, R^(3a) is —C(O)OR¹¹, and R¹¹ is —CH₂CH₂CH₃.

In some embodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein p is 0, 1, 2,or 3. In some embodiments is a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein p is 0. In some embodiments is a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein p is 1. In some embodiments is a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein p is 2. In some embodiments is a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein p is 3. In some embodiments is a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein p is 1, 2, or 3. In some embodiments is a compound of Formula(I), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, wherein p is 1, 2, or 3 and each R⁴ is independently halo,C₁-C₆alkyl, C₁-C₆alkenyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, orC₃-C₈cycloalkyl. In some embodiments is a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein p is 1, 2, or 3 and each R⁴ is independently halo, C₁-C₆alkyl,or C₃-C₈cycloalkyl. In some embodiments is a compound of Formula (I), ora pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein p is 1 and R⁴ is halo, C₁-C₆alkyl, or C₃-C₈cycloalkyl. In someembodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein p is 2 andeach R⁴ is independently halo, C₁-C₆alkyl, or C₃-C₈cycloalkyl. In someembodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein p is 3 andeach R⁴ is independently halo, C₁-C₆alkyl, or C₃-C₈cycloalkyl.

In some embodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein q is 0, 1, 2,or 3. In some embodiments is a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein q is 0. In some embodiments is a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein q is 1. In some embodiments is a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein q is 2. In some embodiments is a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein q is 3. In some embodiments is a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein q is 1, 2, or 3. In some embodiments is a compound of Formula(I), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, wherein q is 1, 2, or 3 and each R⁵ is independently halo,cyano, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, or C₃-C₈cycloalkyl. Insome embodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein q is 1, 2, or3 and each R⁵ is independently halo, cyano, C₁-C₆alkyl, C₁-C₆haloalkyl,or C₁-C₆alkoxy. In some embodiments is a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein q is 1, 2, or 3 and each R⁵ is independently halo or C₁-C₆alkyl.In some embodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein q is 1 and R⁵is halo or C₁-C₆alkyl. In some embodiments is a compound of Formula (I),or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein q is 2 and each R⁵ is independently halo or C₁-C₆alkyl. In someembodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein q is 3 andeach R⁵ is independently halo or C₁-C₆alkyl.

In some embodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein k is 0, 1, 2,3, or 4. In some embodiments is a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein k is 0, 1, 2, or 3. In some embodiments is a compound of Formula(I), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, wherein k is 0, 1, or 2. In some embodiments is a compound ofFormula (I), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein k is 0 or 1. In some embodiments is acompound of Formula (I), or a pharmaceutically acceptable salt, solvate,or stereoisomer thereof, wherein k is 0. In some embodiments is acompound of Formula (I), or a pharmaceutically acceptable salt, solvate,or stereoisomer thereof, wherein k is 1. In some embodiments is acompound of Formula (I), or a pharmaceutically acceptable salt, solvate,or stereoisomer thereof, wherein k is 1 and R³ is halo, C₁-C₆alkyl, orC₁-C₆haloalkyl. In some embodiments is a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein k is 2. In some embodiments is a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein k is 2 and each R³ is independently halo, C₁-C₆alkyl, orC₁-C₆haloalkyl.

In some embodiments, provided herein is a compound of Formula (Ia), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof:

-   wherein:-   is phenyl;-   is a pyridyl ring;-   Z is —(C(R⁶)(R⁷))_(t)—;-   R¹ and R² are selected from (i) and (ii):-   (i) R¹ and R², together with the carbon atom to which they are    attached, form a 4-, 5-, or 6-membered heterocyclyl ring wherein the    4-, 5-, or 6-membered heterocyclyl ring is optionally substituted    with 1 to 4 R^(3a) groups; and-   (ii) R¹ is hydrogen and R² is —S(O)₂R¹⁰, —C₁-C₆alkyl-S(O)₂R¹⁰,    —N(R¹¹)S(O)₂R¹⁰, or —C₁-C₆alkyl-N(R¹¹)S(O)₂R¹⁰;-   each R³ is independently selected from halo and C₁-C₆alkyl;-   each R^(3a) is independently selected from C₁-C₆alkyl,    C₁-C₆haloalkyl, C₂-C₉heteroaryl, (C₂-C₉heteroaryl)-C₁-C₆alkylene-,    oxo, —S(O)₂R¹⁰, —C(O)R¹⁰, —C(O)OR¹¹, and —C(O)N(R¹)₂, wherein    C₂-C₉heteroaryl and (C₂-C₉heteroaryl)-C₁-C₆alkylene- are optionally    substituted with 1 to 3 groups independently selected from halo,    C₁-C₆alkyl, C₁-C₆haloalkyl, and hydroxyl;-   each R⁴ and each R⁵ are each independently selected from halo,    cyano, —OH, C₁-C₆alkyl, C₁-C₆alkenyl, C₁-C₆haloalkyl, C₁-C₆alkoxy,    C₃-C₈cycloalkyl, —N(R⁹)₂, —C(O)R⁸, —C(O)OR⁹, —C(O)N(R⁹)₂,    —N(R⁹)C(O)R⁸, —N(R⁹)SO₂R⁸, —SO₂R⁸, and —SO₂N(R⁸)₂;-   each R⁶ and each R⁷ are each independently hydrogen, halo, or    C₁-C₆alkyl;-   each R⁸ is independently C₁-C₆alkyl or C₁-C₆haloalkyl;-   each R⁹ is independently hydrogen, C₁-C₆alkyl, or C₁-C₆haloalkyl;-   each R¹⁰ is independently C₁-C₆alkyl, C₁-C₆haloalkyl,    C₁-C₆alkyl-O—C₁-C₆alkyl-, C₃-C₈cycloalkyl, C₂-C₉heterocyclyl,    phenyl, (phenyl)-C₁-C₆alkylene-, C₂-C₉heteroaryl, or    (C₂-C₉heteroaryl)-C₁-C₆alkylene-, wherein the C₃-C₈cycloalkyl,    C₂-C₉heterocyclyl, phenyl, (phenyl)-C₁-C₆alkylene-, C₂-C₉heteroaryl,    or (C₂-C₉heteroaryl)-C₁-C₆alkylene- is optionally substituted with 1    to 3 groups selected from halo, C₁-C₆alkyl, C₁-C₆haloalkyl, and    hydroxyl;-   each R¹¹ is independently hydrogen, C₁-C₆alkyl, or C₁-C₆haloalkyl;-   m is 1, 2, or 3;-   n is 1, 2, or 3;-   k is 0, 1, 2, 3, or 4;-   p is 0, 1, 2, 3, or 4;-   q is 0, 1, 2, or 3; and-   t is 0, 1, 2, or 3.

In some embodiments, provided herein is a compound of Formula (Ia), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein each R⁶ and each R⁷ are each independently hydrogen orC₁-C₆alkyl. In some embodiments, provided herein is a compound ofFormula (Ia), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein each R⁶ and each R⁷ are hydrogen. In someembodiments, provided herein is a compound of Formula (Ia), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein each R⁶ and each R⁷ are each independently C₁-C₆alkyl. In someembodiments, provided herein is a compound of Formula (Ia), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein each R⁶ and each R⁷ are —CH₃. In some embodiments, providedherein is a compound of Formula (Ia), or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, wherein each R⁶ and each R⁷ areeach independently halo.

In some embodiments, provided herein is a compound of Formula (Ia), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein t is 0. In some embodiments, provided herein is a compound ofFormula (Ia), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein t is 1, 2, or 3. In some embodiments,provided herein is a compound of Formula (Ia), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein t is 1. Insome embodiments, provided herein is a compound of Formula (Ia), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein t is 2. In some embodiments, provided herein is a compound ofFormula (Ia), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein t is 3.

In some embodiments, provided herein is a compound of Formula (Ia), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein Z is —CH₂—. In some embodiments, provided herein is a compoundof Formula (Ia), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein Z is —CH₂CH₂—. In some embodiments,provided herein is a compound of Formula (Ia), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein Z is—CH₂CH₂CH₂—.

In some embodiments is a compound of Formula (Ia), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein m is 1 and nis 1. In some embodiments is a compound of Formula (Ia), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein m is 2 and n is 1. In some embodiments is a compound of Formula(Ia), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, wherein m is 2 and n is 2. In some embodiments is a compound ofFormula (Ia), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein m is 3 and n is 1. In some embodiments isa compound of Formula (Ia), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein m is 3 and n is 2. In someembodiments is a compound of Formula (Ia), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein m is 3 and nis 3.

In some embodiments is a compound of Formula (Ia), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein R¹ and R²,together with the carbon atom to which they are attached, form a 4-, 5-,or 6-membered heterocyclyl ring, wherein the 4-, 5-, or 6-memberedheterocyclyl ring is optionally substituted with 1 to 4 R^(3a) groups.In some embodiments is a compound of Formula (Ia), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein R¹ and R²,together with the carbon atom to which they are attached, form a4-membered heterocyclyl ring, wherein the 4-membered heterocyclyl ringis optionally substituted with 1 to 4 R^(3a) groups. In some embodimentsis a compound of Formula (Ia), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein R¹ and R², together with thecarbon atom to which they are attached, form a 5-membered heterocyclylring, wherein the 5-membered heterocyclyl ring is optionally substitutedwith 1 to 4 R^(3a) groups. In some embodiments is a compound of Formula(Ia), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, wherein R¹ and R², together with the carbon atom to which theyare attached, form a 6-membered heterocyclyl ring, wherein the6-membered heterocyclyl ring is optionally substituted with 1 to 4R^(3a) groups. In some embodiments is a compound of Formula (Ia), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein R¹ and R², together with the carbon atom to which they areattached, form a 4-, 5-, or 6-membered heterocyclyl ring, wherein the4-, 5-, or 6-membered heterocyclyl ring is optionally substituted with 1or 2 R^(3a) groups. In some embodiments is a compound of Formula (Ia),or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein R¹ and R², together with the carbon atom to which they areattached, form a 4-membered heterocyclyl ring, wherein the 4-memberedheterocyclyl ring is optionally substituted with 1 or 2 R^(3a) groups.In some embodiments is a compound of Formula (Ia), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein R¹ and R²,together with the carbon atom to which they are attached, form a5-membered heterocyclyl ring, wherein the 5-membered heterocyclyl ringis optionally substituted with 1 or 2 R^(3a) groups. In some embodimentsis a compound of Formula (Ia), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein R¹ and R², together with thecarbon atom to which they are attached, form a 6-membered heterocyclylring, wherein the 6-membered heterocyclyl ring is optionally substitutedwith 1 or 2 R^(3a) groups. In some embodiments is a compound of Formula(Ia), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, wherein R¹ and R², together with the carbon atom to which theyare attached, form a 4-, 5-, or 6-membered heterocyclyl ring, whereinthe 4-, 5-, or 6-membered heterocyclyl ring is optionally substitutedwith 1 R^(3a) group. In some embodiments is a compound of Formula (Ia),or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein R¹ and R², together with the carbon atom to which they areattached, form a 4-membered heterocyclyl ring, wherein the 4-memberedheterocyclyl ring is optionally substituted with 1 R^(3a) group. In someembodiments is a compound of Formula (Ia), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein R¹ and R²,together with the carbon atom to which they are attached, form a5-membered heterocyclyl ring, wherein the 5-membered heterocyclyl ringis optionally substituted with 1 R^(3a) group. In some embodiments is acompound of Formula (Ia), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein R¹ and R², together with thecarbon atom to which they are attached, form a 6-membered heterocyclylring, wherein the 6-membered heterocyclyl ring is optionally substitutedwith 1 R^(3a) group.

In some embodiments is a compound of Formula (Ia), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein R¹ and R²,together with the carbon atom to which they are attached, form a 4-, 5-,or 6-membered heterocyclyl ring, wherein the 4-, 5-, or 6-memberedheterocyclyl ring is optionally substituted with 1 or 2 R^(3a) groupsand each R^(3a) is selected from C₁-C₆alkyl, C₁-C₆haloalkyl,C₂-C₉heteroaryl, (C₂-C₉heteroaryl)-C₁-C₆alkylene-, oxo, —S(O)₂R¹⁰,—C(O)R¹⁰, —C(O)OR¹¹, and —C(O)N(R¹)₂, wherein C₂-C₉heteroaryl and(C₂-C₉heteroaryl)-C₁-C₆alkylene- are optionally substituted with 1 to 3groups independently selected from halo, C₁-C₆alkyl, C₁-C₆haloalkyl, andhydroxyl. In some embodiments is a compound of Formula (Ia), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein R¹ and R², together with the carbon atom to which they areattached, form a 4-, 5-, or 6-membered heterocyclyl ring, wherein the4-, 5-, or 6-membered heterocyclyl ring is optionally substituted with 1or 2 R^(3a) groups and each R^(3a) is selected from C₁-C₆alkyl, oxo,—S(O)₂R¹⁰, —C(O)R¹⁰, and —C(O)OR¹¹. In some embodiments is a compound ofFormula (Ia), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein R¹ and R², together with the carbon atomto which they are attached, form a 4-, 5-, or 6-membered heterocyclylring, wherein the 4-, 5-, or 6-membered heterocyclyl ring is optionallysubstituted with 1 or 2 R^(3a) groups and each R^(3a) is selected fromC₁-C₆alkyl, oxo, —S(O)₂R¹⁰, —C(O)R¹⁰, and —C(O)OR¹¹. In some embodimentsis a compound of Formula (Ia), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein R¹ and R², together with thecarbon atom to which they are attached, form a 4-membered heterocyclylring, wherein the 4-membered heterocyclyl ring is optionally substitutedwith 1 or 2 R^(3a) groups and each R^(3a) is selected from C₁-C₆alkyl,oxo, —S(O)₂R¹⁰, —C(O)R¹⁰, and —C(O)OR¹¹. In some embodiments is acompound of Formula (Ia), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein R¹ and R², together with thecarbon atom to which they are attached, form a 5-membered heterocyclylring, wherein the 5-membered heterocyclyl ring is optionally substitutedwith 1 or 2 R^(3a) groups and each R^(3a) is selected from C₁-C₆alkyl,oxo, —S(O)₂R¹⁰, —C(O)R¹⁰, and —C(O)OR¹¹. In some embodiments is acompound of Formula (Ia), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein R¹ and R², together with thecarbon atom to which they are attached, form a 6-membered heterocyclylring, wherein the 6-membered heterocyclyl ring is optionally substitutedwith 1 or 2 R^(3a) groups and each R^(3a) is selected from C₁-C₆alkyl,oxo, —S(O)₂R¹⁰, —C(O)R¹⁰, and —C(O)OR¹¹.

In some embodiments is a compound of Formula (Ia), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein R¹ and R²,together with the carbon atom to which they are attached, form a 4-, 5-,or 6-membered heterocyclyl ring, wherein the 4-, 5-, or 6-memberedheterocyclyl ring is optionally substituted with 1 R^(3a) group andR^(3a) is —S(O)₂R¹⁰. In some embodiments is a compound of Formula (Ia),or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein R¹ and R², together with the carbon atom to which they areattached, form a 4-, 5-, or 6-membered heterocyclyl ring, wherein the4-, 5-, or 6-membered heterocyclyl ring is optionally substituted with 1R^(3a) group, R^(3a) is —S(O)₂R¹⁰, and R¹⁰ is C₁-C₆alkyl,C₁-C₆haloalkyl, C₁-C₆alkyl-O—C₁-C₆alkyl-, C₃-C₈cycloalkyl,C₂-C₉heterocyclyl, C₆-C₁₀aryl, or (C₆-C₁₀aryl)-C₁-C₆alkylene-. In someembodiments is a compound of Formula (Ia), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein R¹ and R²,together with the carbon atom to which they are attached, form a 4-, 5-,or 6-membered heterocyclyl ring, wherein the 4-, 5-, or 6-memberedheterocyclyl ring is optionally substituted with 1 R^(3a) group, R^(3a)is —S(O)₂R¹⁰, and R¹⁰ is C₁-C₆alkyl or C₃-C₈cycloalkyl. In someembodiments is a compound of Formula (Ia), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein R¹ and R²,together with the carbon atom to which they are attached, form a 4-, 5-,or 6-membered heterocyclyl ring, wherein the 4-, 5-, or 6-memberedheterocyclyl ring is optionally substituted with 1 R^(3a) group, R^(3a)is —S(O)₂R¹⁰, and R¹⁰ is C₁-C₆alkyl. In some embodiments is a compoundof Formula (Ia), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein R¹ and R², together with the carbon atomto which they are attached, form a 4-, 5-, or 6-membered heterocyclylring, wherein the 4-, 5-, or 6-membered heterocyclyl ring is optionallysubstituted with 1 R^(3a) group, R^(3a) is —S(O)₂R¹⁰, and R¹⁰ is —CH₃.In some embodiments is a compound of Formula (Ia), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein R¹ and R²,together with the carbon atom to which they are attached, form a 4-, 5-,or 6-membered heterocyclyl ring, wherein the 4-, 5-, or 6-memberedheterocyclyl ring is optionally substituted with 1 R^(3a) group, R^(3a)is —S(O)₂R¹⁰, and R¹⁰ is —CH₂CH₃. In some embodiments is a compound ofFormula (Ia), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein R¹ and R², together with the carbon atomto which they are attached, form a 4-, 5-, or 6-membered heterocyclylring, wherein the 4-, 5-, or 6-membered heterocyclyl ring is optionallysubstituted with 1 R^(3a) group, R^(3a) is —S(O)₂R¹⁰, and R¹⁰ is—CH₂CH₂CH₃. In some embodiments is a compound of Formula (Ia), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein R¹ and R², together with the carbon atom to which they areattached, form a 4-, 5-, or 6-membered heterocyclyl ring, wherein the4-, 5-, or 6-membered heterocyclyl ring is optionally substituted with 1R^(3a) group, R^(3a) is —S(O)₂R¹⁰, and R¹⁰ is C₃-C₈cycloalkyl. In someembodiments is a compound of Formula (Ia), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein R¹ and R²,together with the carbon atom to which they are attached, form a 4-, 5-,or 6-membered heterocyclyl ring, wherein the 4-, 5-, or 6-memberedheterocyclyl ring is optionally substituted with 1 R^(3a) group, R^(3a)is —S(O)₂R¹⁰, and R¹⁰ is cyclopropyl.

In some embodiments is a compound of Formula (Ia), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein R¹ and R²,together with the carbon atom to which they are attached, form a 4-, 5-,or 6-membered heterocyclyl ring, wherein the 4-, 5-, or 6-memberedheterocyclyl ring is optionally substituted with 1 R^(3a) group andR^(3a) is —C(O)R¹⁰. In some embodiments is a compound of Formula (Ia),or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein R¹ and R², together with the carbon atom to which they areattached, form a 4-, 5-, or 6-membered heterocyclyl ring, wherein the4-, 5-, or 6-membered heterocyclyl ring is optionally substituted with 1R^(3a) group, R^(3a) is —C(O)R¹⁰, and R¹⁰ is C₁-C₆alkyl, C₁-C₆haloalkyl,C₁-C₆alkyl-O—C₁-C₆alkyl-, C₃-C₈cycloalkyl, C₂-C₉heterocyclyl,C₆-C₁₀aryl, or (C₆-C₁₀aryl)-C₁-C₆alkylene-. In some embodiments is acompound of Formula (Ia), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein R¹ and R², together with thecarbon atom to which they are attached, form a 4-, 5-, or 6-memberedheterocyclyl ring, wherein the 4-, 5-, or 6-membered heterocyclyl ringis optionally substituted with 1 R^(3a) group, R^(3a) is —C(O)R¹⁰, andR¹⁰ is C₁-C₆alkyl. In some embodiments is a compound of Formula (Ia), ora pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein R¹ and R², together with the carbon atom to which they areattached, form a 4-, 5-, or 6-membered heterocyclyl ring, wherein the4-, 5-, or 6-membered heterocyclyl ring is optionally substituted with 1R^(3a) group, R^(3a) is —C(O)R¹⁰, and R¹⁰ is —CH₃. In some embodimentsis a compound of Formula (Ia), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein R¹ and R², together with thecarbon atom to which they are attached, form a 4-, 5-, or 6-memberedheterocyclyl ring, wherein the 4-, 5-, or 6-membered heterocyclyl ringis optionally substituted with 1 R^(3a) group, R^(3a) is —C(O)R¹⁰, andR¹⁰ is —CH₂CH₃. In some embodiments is a compound of Formula (Ia), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein R¹ and R², together with the carbon atom to which they areattached, form a 4-, 5-, or 6-membered heterocyclyl ring, wherein the4-, 5-, or 6-membered heterocyclyl ring is optionally substituted with 1R^(3a) group, R^(3a) is —C(O)R¹⁰, and R¹⁰ is —CH₂CH₂CH₃.

In some embodiments is a compound of Formula (Ia), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein R¹ and R²,together with the carbon atom to which they are attached, form a 4-, 5-,or 6-membered heterocyclyl ring, wherein the 4-, 5-, or 6-memberedheterocyclyl ring is optionally substituted with 1 R^(3a) group andR^(3a) is —C(O)OR¹¹. In some embodiments is a compound of Formula (Ia),or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein R¹ and R², together with the carbon atom to which they areattached, form a 4-, 5-, or 6-membered heterocyclyl ring, wherein the4-, 5-, or 6-membered heterocyclyl ring is optionally substituted with 1R^(3a) group, R^(3a) is —C(O)OR¹¹, and R¹¹ is C₁-C₆alkyl. In someembodiments is a compound of Formula (Ia), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein R¹ and R²,together with the carbon atom to which they are attached, form a 4-, 5-,or 6-membered heterocyclyl ring, wherein the 4-, 5-, or 6-memberedheterocyclyl ring is optionally substituted with 1 R^(3a) group, R^(3a)is —C(O)OR¹¹, and R¹¹ is —CH₃. In some embodiments is a compound ofFormula (Ia), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein R¹ and R², together with the carbon atomto which they are attached, form a 4-, 5-, or 6-membered heterocyclylring, wherein the 4-, 5-, or 6-membered heterocyclyl ring is optionallysubstituted with 1 R^(3a) group, R^(3a) is —C(O)OR¹¹, and R¹¹ is—CH₂CH₃. In some embodiments is a compound of Formula (Ia), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein R¹ and R², together with the carbon atom to which they areattached, form a 4-, 5-, or 6-membered heterocyclyl ring, wherein the4-, 5-, or 6-membered heterocyclyl ring is optionally substituted with 1R^(3a) group, R^(3a) is —C(O)OR¹¹, and R¹¹ is —CH₂CH₂CH₃.

In some embodiments is a compound of Formula (Ia), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein p is 0, 1, 2,or 3. In some embodiments is a compound of Formula (Ia), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein p is 0.

In some embodiments is a compound of Formula (Ia), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein p is 1. Insome embodiments is a compound of Formula (Ia), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein p is 2. Insome embodiments is a compound of Formula (Ia), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein p is 3. Insome embodiments is a compound of Formula (Ia), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein p is 1, 2, or3. In some embodiments is a compound of Formula (Ia), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein p is 1, 2, or 3 and each R⁴ is independently halo, C₁-C₆alkyl,C₁-C₆alkenyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, or C₃-C₈cycloalkyl. In someembodiments is a compound of Formula (Ia), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein p is 1, 2, or3 and each R⁴ is independently halo, C₁-C₆alkyl, or C₃-C₈cycloalkyl. Insome embodiments is a compound of Formula (Ia), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein p is 1 and R⁴is halo, C₁-C₆alkyl, or C₃-C₈cycloalkyl. In some embodiments is acompound of Formula (Ia), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein p is 2 and each R⁴ isindependently halo, C₁-C₆alkyl, or C₃-C₈cycloalkyl. In some embodimentsis a compound of Formula (Ia), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein p is 3 and each R⁴ isindependently halo, C₁-C₆alkyl, or C₃-C₈cycloalkyl.

In some embodiments is a compound of Formula (Ia), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein q is 0, 1, or2. In some embodiments is a compound of Formula (Ia), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein q is 0. In some embodiments is a compound of Formula (Ia), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein q is 1. In some embodiments is a compound of Formula (Ia), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein q is 2. In some embodiments is a compound of Formula (Ia), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein q is 3. In some embodiments is a compound of Formula (Ia), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein q is 1, 2, or 3 and each R⁵ is independently halo, cyano,C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, or C₃-C₈cycloalkyl. In someembodiments is a compound of Formula (Ia), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein q is 1, 2, or3 and each R⁵ is independently halo, cyano, C₁-C₆alkyl, C₁-C₆haloalkyl,or C₁-C₆alkoxy. In some embodiments is a compound of Formula (Ia), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein q is 1, 2, or 3 and each R⁵ is independently halo or C₁-C₆alkyl.In some embodiments is a compound of Formula (Ia), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein q is 1 and R⁵is halo or C₁-C₆alkyl. In some embodiments is a compound of Formula(Ia), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, wherein q is 2 and each R⁵ is independently halo or C₁-C₆alkyl.In some embodiments is a compound of Formula (Ia), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein q is 3 andeach R⁵ is independently halo or C₁-C₆alkyl.

In some embodiments is a compound of Formula (Ia), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein k is 0, 1, 2,3, or 4. In some embodiments is a compound of Formula (Ia), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein k is 0, 1, 2, or 3. In some embodiments is a compound of Formula(Ia), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, wherein k is 0, 1, or 2. In some embodiments is a compound ofFormula (Ia), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein k is 0 or 1. In some embodiments is acompound of Formula (Ia), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein k is 0. In some embodiments isa compound of Formula (Ia), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein k is 1. In some embodiments isa compound of Formula (Ia), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein k is 1 and R³ is halo,C₁-C₆alkyl, or C₁-C₆haloalkyl. In some embodiments is a compound ofFormula (Ia), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein k is 2. In some embodiments is a compoundof Formula (Ia), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein k is 2 and each R³ is independently halo,C₁-C₆alkyl, or C₁-C₆haloalkyl.

In some embodiments, provided herein is a compound of Formula (Ib), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof:

wherein:

-   is a pyridyl ring;-   is phenyl;-   Z is —(C(R⁶)(R⁷))_(t)—;-   R¹ and R² are selected from (i) and (ii):-   (i) R¹ and R², together with the carbon atom to which they are    attached, form a 4-, 5-, or 6-membered heterocyclyl ring wherein the    4-, 5-, or 6-membered heterocyclyl ring is optionally substituted    with 1 to 4 R^(3a) groups; and-   (ii) R¹ is hydrogen and R² is —S(O)₂R¹⁰, —C₁-C₆alkyl-S(O)₂R¹⁰,    —N(R¹¹)S(O)₂R¹⁰, or —C₁-C₆alkyl-N(R¹¹)S(O)₂R¹⁰;-   each R³ is independently selected from halo and C₁-C₆alkyl;-   each R^(3a) is independently selected from C₁-C₆alkyl,    C₁-C₆haloalkyl, C₂-C₉heteroaryl, (C₂-C₉heteroaryl)-C₁-C₆alkylene-,    oxo, —S(O)₂R¹⁰, —C(O)R¹⁰, —C(O)OR¹¹, and —C(O)N(R¹)₂ wherein    C₂-C₉heteroaryl and (C₂-C₉heteroaryl)-C₁-C₆alkylene- are optionally    substituted with 1 to 3 groups independently selected from halo,    C₁-C₆alkyl, C₁-C₆haloalkyl, and hydroxyl;-   each R⁴ and each R⁵ are each independently selected from halo,    cyano, —OH, C₁-C₆alkyl, C₁-C₆alkenyl, C₁-C₆haloalkyl, C₁-C₆alkoxy,    C₃-C₈cycloalkyl, —N(R⁹)₂, —C(O)R⁸, —C(O)OR⁹, —C(O)N(R⁹)₂,    —N(R⁹)C(O)R⁸, —N(R⁹)SO₂R⁸, —SO₂R⁸, and —SO₂N(R⁸)₂;-   each R⁶ and each R⁷ are each independently hydrogen, halo, or    C₁-C₆alkyl;-   each R⁸ is independently C₁-C₆alkyl or C₁-C₆haloalkyl;-   each R⁹ is independently hydrogen, C₁-C₆alkyl, or C₁-C₆haloalkyl;-   each R¹⁰ is independently C₁-C₆alkyl, C₁-C₆haloalkyl,    C₁-C₆alkyl-O—C₁-C₆alkyl-, C₃-C₈cycloalkyl, C₂-C₉heterocyclyl,    phenyl, (phenyl)-C₁-C₆alkylene-, C₂-C₉heteroaryl, or    (C₂-C₉heteroaryl)-C₁-C₆alkylene-, wherein the C₃-C₈cycloalkyl,    C₂-C₉heterocyclyl, phenyl, (phenyl)-C₁-C₆alkylene-, C₂-C₉heteroaryl,    or (C₂-C₉heteroaryl)-C₁-C₆alkylene- is optionally substituted with 1    to 3 groups selected from halo, C₁-C₆alkyl, C₁-C₆haloalkyl, and    hydroxyl;-   each R¹¹ is independently hydrogen, C₁-C₆alkyl, or C₁-C₆haloalkyl;-   m is 1, 2, or 3;-   n is 1, 2, or 3;-   k is 0, 1, 2, 3, or 4;-   p is 0, 1, 2, or 3;-   q is 0, 1, 2, 3, or 4; and-   t is 0, 1, 2, or 3.

In some embodiments, provided herein is a compound of Formula (Ib), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein each R⁶ and each R⁷ are each independently hydrogen orC₁-C₆alkyl. In some embodiments, provided herein is a compound ofFormula (Ib), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein each R⁶ and each R⁷ are hydrogen. In someembodiments, provided herein is a compound of Formula (Ib), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein each R⁶ and each R⁷ are each independently C₁-C₆alkyl. In someembodiments, provided herein is a compound of Formula (Ib), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein each R⁶ and each R⁷ are —CH₃. In some embodiments, providedherein is a compound of Formula (Ib), or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, wherein each R⁶ and each R⁷ areeach independently halo.

In some embodiments, provided herein is a compound of Formula (Ib), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein t is 0. In some embodiments, provided herein is a compound ofFormula (Ib), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein t is 1, 2, or 3. In some embodiments,provided herein is a compound of Formula (Ib), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein t is 1. Insome embodiments, provided herein is a compound of Formula (Ib), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein t is 2. In some embodiments, provided herein is a compound ofFormula (Ib), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein t is 3.

In some embodiments, provided herein is a compound of Formula (Ib), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein Z is —CH₂—. In some embodiments, provided herein is a compoundof Formula (Ib), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein Z is —CH₂CH₂—. In some embodiments,provided herein is a compound of Formula (Ib), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein Z is—CH₂CH₂CH₂—.

In some embodiments is a compound of Formula (Ib), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein m is 1 and nis 1. In some embodiments is a compound of Formula (Ib), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein m is 2 and n is 1. In some embodiments is a compound of Formula(Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, wherein m is 2 and n is 2. In some embodiments is a compound ofFormula (Ib), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein m is 3 and n is 1. In some embodiments isa compound of Formula (Ib), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein m is 3 and n is 2. In someembodiments is a compound of Formula (Ib), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein m is 3 and nis 3.

In some embodiments is a compound of Formula (Ib), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein R¹ and R²,together with the carbon atom to which they are attached, form a 4-, 5-,or 6-membered heterocyclyl ring, wherein the 4-, 5-, or 6-memberedheterocyclyl ring is optionally substituted with 1 to 4 R^(3a) groups.In some embodiments is a compound of Formula (Ib), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein R¹ and R²,together with the carbon atom to which they are attached, form a4-membered heterocyclyl ring, wherein the 4-membered heterocyclyl ringis optionally substituted with 1 to 4 R^(3a) groups. In some embodimentsis a compound of Formula (Ib), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein R¹ and R², together with thecarbon atom to which they are attached, form a 5-membered heterocyclylring, wherein the 5-membered heterocyclyl ring is optionally substitutedwith 1 to 4 R^(3a) groups. In some embodiments is a compound of Formula(Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, wherein R¹ and R², together with the carbon atom to which theyare attached, form a 6-membered heterocyclyl ring, wherein the6-membered heterocyclyl ring is optionally substituted with 1 to 4R^(3a) groups. In some embodiments is a compound of Formula (Ib), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein R¹ and R², together with the carbon atom to which they areattached, form a 4-, 5-, or 6-membered heterocyclyl ring, wherein the4-, 5-, or 6-membered heterocyclyl ring is optionally substituted with 1or 2 R^(3a) groups. In some embodiments is a compound of Formula (Ib),or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein R¹ and R², together with the carbon atom to which they areattached, form a 4-membered heterocyclyl ring, wherein the 4-memberedheterocyclyl ring is optionally substituted with 1 or 2 R^(3a) groups.In some embodiments is a compound of Formula (Ib), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein R¹ and R²,together with the carbon atom to which they are attached, form a5-membered heterocyclyl ring, wherein the 5-membered heterocyclyl ringis optionally substituted with 1 or 2 R^(3a) groups. In some embodimentsis a compound of Formula (Ib), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein R¹ and R², together with thecarbon atom to which they are attached, form a 6-membered heterocyclylring, wherein the 6-membered heterocyclyl ring is optionally substitutedwith 1 or 2 R^(3a) groups. In some embodiments is a compound of Formula(Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, wherein R¹ and R², together with the carbon atom to which theyare attached, form a 4-, 5-, or 6-membered heterocyclyl ring, whereinthe 4-, 5-, or 6-membered heterocyclyl ring is optionally substitutedwith 1 R^(3a) group. In some embodiments is a compound of Formula (Ib),or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein R¹ and R², together with the carbon atom to which they areattached, form a 4-membered heterocyclyl ring, wherein the 4-memberedheterocyclyl ring is optionally substituted with 1 R^(3a) group. In someembodiments is a compound of Formula (Ib), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein R¹ and R²,together with the carbon atom to which they are attached, form a5-membered heterocyclyl ring, wherein the 5-membered heterocyclyl ringis optionally substituted with 1 R^(3a) group. In some embodiments is acompound of Formula (Ib), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein R¹ and R², together with thecarbon atom to which they are attached, form a 6-membered heterocyclylring, wherein the 6-membered heterocyclyl ring is optionally substitutedwith 1 R^(3a) group.

In some embodiments is a compound of Formula (Ib), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein R¹ and R²,together with the carbon atom to which they are attached, form a 4-, 5-,or 6-membered heterocyclyl ring, wherein the 4-, 5-, or 6-memberedheterocyclyl ring is optionally substituted with 1 or 2 R^(3a) groupsand each R^(3a) is selected from C₁-C₆alkyl, C₁-C₆haloalkyl,C₂-C₉heteroaryl, (C₂-C₉heteroaryl)-C₁-C₆alkylene-, oxo, —S(O)₂R¹⁰,—C(O)R¹⁰, —C(O)OR¹¹, and —C(O)N(R¹)₂, wherein C₂-C₉heteroaryl and(C₂-C₉heteroaryl)-C₁-C₆alkylene- are optionally substituted with 1 to 3groups independently selected from halo, C₁-C₆alkyl, C₁-C₆haloalkyl, andhydroxyl. In some embodiments is a compound of Formula (Ib), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein R¹ and R², together with the carbon atom to which they areattached, form a 4-, 5-, or 6-membered heterocyclyl ring, wherein the4-, 5-, or 6-membered heterocyclyl ring is optionally substituted with 1or 2 R³ groups and each R^(3a) is selected from C₁-C₆alkyl, oxo,—S(O)₂R¹⁰, —C(O)R¹⁰, and —C(O)OR¹¹. In some embodiments is a compound ofFormula (Ib), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein R¹ and R², together with the carbon atomto which they are attached, form a 4-, 5-, or 6-membered heterocyclylring, wherein the 4-, 5-, or 6-membered heterocyclyl ring is optionallysubstituted with 1 or 2 R^(3a) groups and each R^(3a) is selected fromC₁-C₆alkyl, oxo, —S(O)₂R¹⁰, —C(O)R¹⁰, and —C(O)OR¹¹. In some embodimentsis a compound of Formula (Ib), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein R¹ and R², together with thecarbon atom to which they are attached, form a 4-membered heterocyclylring, wherein the 4-membered heterocyclyl ring is optionally substitutedwith 1 or 2 R^(3a) groups and each R^(3a) is selected from C₁-C₆alkyl,oxo, —S(O)₂R¹⁰, —C(O)R¹⁰, and —C(O)OR¹¹. In some embodiments is acompound of Formula (Ib), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein R¹ and R², together with thecarbon atom to which they are attached, form a 5-membered heterocyclylring, wherein the 5-membered heterocyclyl ring is optionally substitutedwith 1 or 2 R^(3a) groups and each R^(3a) is selected from C₁-C₆alkyl,oxo, —S(O)₂R¹⁰, —C(O)R¹⁰, and —C(O)OR¹¹. In some embodiments is acompound of Formula (Ib), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein R¹ and R², together with thecarbon atom to which they are attached, form a 6-membered heterocyclylring, wherein the 6-membered heterocyclyl ring is optionally substitutedwith 1 or 2 R^(3a) groups and each R^(3a) is selected from C₁-C₆alkyl,oxo, —S(O)₂R¹⁰, —C(O)R¹⁰, and —C(O)OR¹¹.

In some embodiments is a compound of Formula (Ib), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein R¹ and R²,together with the carbon atom to which they are attached, form a 4-, 5-,or 6-membered heterocyclyl ring, wherein the 4-, 5-, or 6-memberedheterocyclyl ring is optionally substituted with 1 R^(3a) group andR^(3a) is —S(O)₂R¹⁰. In some embodiments is a compound of Formula (Ib),or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein R¹ and R², together with the carbon atom to which they areattached, form a 4-, 5-, or 6-membered heterocyclyl ring, wherein the4-, 5-, or 6-membered heterocyclyl ring is optionally substituted with 1R^(3a) group, R^(3a) is —S(O)₂R¹⁰, and R¹⁰ is C₁-C₆alkyl,C₁-C₆haloalkyl, C₁-C₆alkyl-O—C₁-C₆alkyl-, C₃-C₈cycloalkyl,C₂-C₉heterocyclyl, C₆-C₁₀aryl, or (C₆-C₁₀aryl)-C₁-C₆alkylene-. In someembodiments is a compound of Formula (Ib), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein R¹ and R²,together with the carbon atom to which they are attached, form a 4-, 5-,or 6-membered heterocyclyl ring, wherein the 4-, 5-, or 6-memberedheterocyclyl ring is optionally substituted with 1 R^(3a) group, R^(3a)is —S(O)₂R¹⁰, and R¹⁰ is C₁-C₆alkyl or C₃-C₈cycloalkyl. In someembodiments is a compound of Formula (Ib), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein R¹ and R²,together with the carbon atom to which they are attached, form a 4-, 5-,or 6-membered heterocyclyl ring, wherein the 4-, 5-, or 6-memberedheterocyclyl ring is optionally substituted with 1 R^(3a) group, R^(3a)is —S(O)₂R¹⁰, and R¹⁰ is C₁-C₆alkyl. In some embodiments is a compoundof Formula (Ib), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein R¹ and R², together with the carbon atomto which they are attached, form a 4-, 5-, or 6-membered heterocyclylring, wherein the 4-, 5-, or 6-membered heterocyclyl ring is optionallysubstituted with 1 R^(3a) group, R^(3a) is —S(O)₂R¹⁰, and R¹⁰ is —CH₃.In some embodiments is a compound of Formula (Ib), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein R¹ and R²,together with the carbon atom to which they are attached, form a 4-, 5-,or 6-membered heterocyclyl ring, wherein the 4-, 5-, or 6-memberedheterocyclyl ring is optionally substituted with 1 R^(3a) group, R^(3a)is —S(O)₂R¹⁰, and R¹⁰ is —CH₂CH₃. In some embodiments is a compound ofFormula (Ib), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein R¹ and R², together with the carbon atomto which they are attached, form a 4-, 5-, or 6-membered heterocyclylring, wherein the 4-, 5-, or 6-membered heterocyclyl ring is optionallysubstituted with 1 R^(3a) group, R^(3a) is —S(O)₂R¹⁰, and R¹⁰ is—CH₂CH₂CH₃. In some embodiments is a compound of Formula (Ib), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein R¹ and R², together with the carbon atom to which they areattached, form a 4-, 5-, or 6-membered heterocyclyl ring, wherein the4-, 5-, or 6-membered heterocyclyl ring is optionally substituted with 1R^(3a) group, R^(3a) is —S(O)₂R¹⁰, and R¹⁰ is C₃-C₈cycloalkyl. In someembodiments is a compound of Formula (Ib), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein R¹ and R²,together with the carbon atom to which they are attached, form a 4-, 5-,or 6-membered heterocyclyl ring, wherein the 4-, 5-, or 6-memberedheterocyclyl ring is optionally substituted with 1 R^(3a) group, R^(3a)is —S(O)₂R¹⁰, and R¹⁰ is cyclopropyl.

In some embodiments is a compound of Formula (Ib), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein R¹ and R²,together with the carbon atom to which they are attached, form a 4-, 5-,or 6-membered heterocyclyl ring, wherein the 4-, 5-, or 6-memberedheterocyclyl ring is optionally substituted with 1 R^(3a) group andR^(3a) is —C(O)R¹⁰. In some embodiments is a compound of Formula (Ib),or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein R¹ and R², together with the carbon atom to which they areattached, form a 4-, 5-, or 6-membered heterocyclyl ring, wherein the4-, 5-, or 6-membered heterocyclyl ring is optionally substituted with 1R^(3a) group, R^(3a) is —C(O)R¹⁰, and R¹⁰ is C₁-C₆alkyl, C₁-C₆haloalkyl,C₁-C₆alkyl-O—C₁-C₆alkyl-, C₃-C₈cycloalkyl, C₂-C₉heterocyclyl,C₆-C₁₀aryl, or (C₆-C₁₀aryl)-C₁-C₆alkylene-. In some embodiments is acompound of Formula (Ib), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein R¹ and R², together with thecarbon atom to which they are attached, form a 4-, 5-, or 6-memberedheterocyclyl ring, wherein the 4-, 5-, or 6-membered heterocyclyl ringis optionally substituted with 1 R^(3a) group, R^(3a) is —C(O)R¹⁰, andR¹⁰ is C₁-C₆alkyl. In some embodiments is a compound of Formula (Ib), ora pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein R¹ and R², together with the carbon atom to which they areattached, form a 4-, 5-, or 6-membered heterocyclyl ring, wherein the4-, 5-, or 6-membered heterocyclyl ring is optionally substituted with 1R^(3a) group, R^(3a) is —C(O)R¹⁰, and R¹⁰ is —CH₃. In some embodimentsis a compound of Formula (Ib), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein R¹ and R², together with thecarbon atom to which they are attached, form a 4-, 5-, or 6-memberedheterocyclyl ring, wherein the 4-, 5-, or 6-membered heterocyclyl ringis optionally substituted with 1 R^(3a) group, R^(3a) is —C(O)R¹⁰, andR¹⁰ is —CH₂CH₃. In some embodiments is a compound of Formula (Ib), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein R¹ and R², together with the carbon atom to which they areattached, form a 4-, 5-, or 6-membered heterocyclyl ring, wherein the4-, 5-, or 6-membered heterocyclyl ring is optionally substituted with 1R^(3a) group, R^(3a) is —C(O)R¹⁰, and R¹⁰ is —CH₂CH₂CH₃.

In some embodiments is a compound of Formula (Ib), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein R¹ and R²,together with the carbon atom to which they are attached, form a 4-, 5-,or 6-membered heterocyclyl ring, wherein the 4-, 5-, or 6-memberedheterocyclyl ring is optionally substituted with 1 R^(3a) group andR^(3a) is —C(O)OR¹¹. In some embodiments is a compound of Formula (Ib),or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein R¹ and R², together with the carbon atom to which they areattached, form a 4-, 5-, or 6-membered heterocyclyl ring, wherein the4-, 5-, or 6-membered heterocyclyl ring is optionally substituted with 1R^(3a) group, R^(3a) is —C(O)OR¹¹, and R¹¹ is C₁-C₆alkyl. In someembodiments is a compound of Formula (Ib), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein R¹ and R²,together with the carbon atom to which they are attached, form a 4-, 5-,or 6-membered heterocyclyl ring, wherein the 4-, 5-, or 6-memberedheterocyclyl ring is optionally substituted with 1 R^(3a) group, R^(3a)is —C(O)OR¹¹, and R¹¹ is —CH₃. In some embodiments is a compound ofFormula (Ib), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein R¹ and R², together with the carbon atomto which they are attached, form a 4-, 5-, or 6-membered heterocyclylring, wherein the 4-, 5-, or 6-membered heterocyclyl ring is optionallysubstituted with 1 R^(3a) group, R^(3a) is —C(O)OR¹¹, and R¹¹ is—CH₂CH₃. In some embodiments is a compound of Formula (Ib), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein R¹ and R², together with the carbon atom to which they areattached, form a 4-, 5-, or 6-membered heterocyclyl ring, wherein the4-, 5-, or 6-membered heterocyclyl ring is optionally substituted with 1R^(3a) group, R^(3a) is —C(O)OR¹¹, and R¹¹ is —CH₂CH₂CH₃.

In some embodiments is a compound of Formula (Ib), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein p is 0, 1, or2. In some embodiments is a compound of Formula (Ib), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein p is 0.

In some embodiments is a compound of Formula (Ib), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein p is 1. Insome embodiments is a compound of Formula (Ib), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein p is 2. Insome embodiments is a compound of Formula (Ib), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein p is 3. Insome embodiments is a compound of Formula (Ib), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein p is 1, 2, or3. In some embodiments is a compound of Formula (Ib), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein p is 1, 2, or 3 and each R⁴ is independently halo, C₁-C₆alkyl,C₁-C₆alkenyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, or C₃-C₈cycloalkyl. In someembodiments is a compound of Formula (Ib), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein p is 1, 2, or3 and each R⁴ is independently halo, C₁-C₆alkyl, or C₃-C₈cycloalkyl. Insome embodiments is a compound of Formula (Ib), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein p is 1 and R⁴is halo, C₁-C₆alkyl, or C₃-C₈cycloalkyl. In some embodiments is acompound of Formula (Ib), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein p is 2 and each R⁴ isindependently halo, C₁-C₆alkyl, or C₃-C₈cycloalkyl. In some embodimentsis a compound of Formula (Ib), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein p is 3 and each R⁴ isindependently halo, C₁-C₆alkyl, or C₃-C₈cycloalkyl.

In some embodiments is a compound of Formula (Ib), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein q is 0, 1, 2,or 3. In some embodiments is a compound of Formula (Ib), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein q is 0. In some embodiments is a compound of Formula (Ib), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein q is 1. In some embodiments is a compound of Formula (Ib), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein q is 2. In some embodiments is a compound of Formula (Ib), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein q is 3. In some embodiments is a compound of Formula (Ib), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein q is 1, 2, or 3. In some embodiments is a compound of Formula(Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, wherein q is 1, 2, or 3 and each R⁵ is independently halo,cyano, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, or C₃-C₈cycloalkyl. Insome embodiments is a compound of Formula (Ib), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein q is 1, 2, or3 and each R⁵ is independently halo, cyano, C₁-C₆alkyl, C₁-C₆haloalkyl,or C₁-C₆alkoxy. In some embodiments is a compound of Formula (Ib), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein q is 1, 2, or 3 and each R⁵ is independently halo or C₁-C₆alkyl.In some embodiments is a compound of Formula (Ib), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein q is 1 and R⁵is halo or C₁-C₆alkyl. In some embodiments is a compound of Formula(Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, wherein q is 2 and each R⁵ is independently halo or C₁-C₆alkyl.In some embodiments is a compound of Formula (Ib), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein q is 3 andeach R⁵ is independently halo or C₁-C₆alkyl.

In some embodiments is a compound of Formula (Ib), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein k is 0, 1, 2,3, or 4. In some embodiments is a compound of Formula (Ib), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein k is 0, 1, 2, or 3. In some embodiments is a compound of Formula(Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, wherein k is 0, 1, or 2. In some embodiments is a compound ofFormula (Ib), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein k is 0 or 1. In some embodiments is acompound of Formula (Ib), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein k is 0. In some embodiments isa compound of Formula (Ib), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein k is 1. In some embodiments isa compound of Formula (Ib), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein k is 1 and R³ is halo,C₁-C₆alkyl, or C₁-C₆haloalkyl. In some embodiments is a compound ofFormula (Ib), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein k is 2. In some embodiments is a compoundof Formula (Ib), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein k is 2 and each R³ is independently halo,C₁-C₆alkyl, or C₁-C₆haloalkyl.

In some embodiments, provided herein is a compound of Formula (II), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof:

wherein:

-   -   X is —O—, —NH—, —N(R^(3a))—, —S—, —S(O)—, or —S(O)₂—;    -   Z is —(C(R⁶)(R⁷))_(t)—;    -   each R³ is independently selected from halo and C₁-C₆alkyl;    -   R^(3a) is selected from C₁-C₆alkyl, C₁-C₆haloalkyl,        C₂-C₉heteroaryl, (C₂-C₉heteroaryl)-C₁-C₆alkylene-, oxo,        —S(O)₂R¹⁰, —C(O)R¹⁰, —C(O)OR¹¹, and —C(O)N(R¹)₂, wherein        C₂-C₉heteroaryl and (C₂-C₉heteroaryl)-C₁-C₆alkylene- are        optionally substituted with 1 to 3 groups independently selected        from halo, C₁-C₆alkyl, C₁-C₆haloalkyl, and hydroxyl;    -   each R⁴ and each R⁵ are each independently selected from halo,        cyano, —OH, C₁-C₆alkyl, C₁-C₆alkenyl, C₁-C₆haloalkyl,        C₁-C₆alkoxy, C₃-C₈cycloalkyl, —N(R⁹)₂, —C(O)R⁸, —C(O)OR⁹,        —C(O)N(R⁹)₂, —N(R⁹)C(O)R⁸, —N(R⁹)SO₂R⁸, —SO₂R⁸, and —SO₂N(R⁸)₂;    -   each R⁶ and each R⁷ are each independently hydrogen, halo, or        C₁-C₆alkyl;    -   each R⁸ is independently C₁-C₆alkyl or C₁-C₆haloalkyl;    -   each R⁹ is independently hydrogen, C₁-C₆alkyl, or        C₁-C₆haloalkyl;    -   R¹⁰ is C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkyl-O—C₁-C₆alkyl-,        C₃-C₈cycloalkyl, C₂-C₉heterocyclyl, phenyl,        (phenyl)-C₁-C₆alkylene-, C₂-C₉heteroaryl, or        (C₂-C₉heteroaryl)-C₁-C₆alkylene-, wherein the C₃-C₈cycloalkyl,        C₂-C₉heterocyclyl, phenyl, (phenyl)-C₁-C₆alkylene-,        C₂-C₉heteroaryl, or (C₂-C₉heteroaryl)-C₁-C₆alkylene- is        optionally substituted with 1 to 3 groups selected from halo,        C₁-C₆alkyl, C₁-C₆haloalkyl, and hydroxyl;    -   R¹¹ is independently hydrogen, C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   a is 1 or 2;    -   b is 1 or 2;    -   m is 1, 2, or 3;    -   n is 1, 2, or 3;    -   k is 0, 1, 2, 3, or 4;    -   p is 0, 1, 2, 3, or 4;    -   q is 0, 1, 2, 3 or 4; and    -   t is 0, 1, 2, or 3.

In some embodiments, provided herein is a compound of Formula (II), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein each R⁶ and each R⁷ are each independently hydrogen orC₁-C₆alkyl. In some embodiments, provided herein is a compound ofFormula (II), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein each R⁶ and each R⁷ are hydrogen. In someembodiments, provided herein is a compound of Formula (II), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein each R⁶ and each R⁷ are each independently C₁-C₆alkyl. In someembodiments, provided herein is a compound of Formula (II), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein each R⁶ and each R⁷ are —CH₃. In some embodiments, providedherein is a compound of Formula (II), or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, wherein each R⁶ and each R⁷ areeach independently halo.

In some embodiments, provided herein is a compound of Formula (II), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein t is 0. In some embodiments, provided herein is a compound ofFormula (II), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein t is 1, 2, or 3. In some embodiments,provided herein is a compound of Formula (II), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein t is 1. Insome embodiments, provided herein is a compound of Formula (II), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein t is 2. In some embodiments, provided herein is a compound ofFormula (II), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein t is 3.

In some embodiments, provided herein is a compound of Formula (II), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein Z is —CH₂—. In some embodiments, provided herein is a compoundof Formula (II), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein Z is —CH₂CH₂—. In some embodiments,provided herein is a compound of Formula (II), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein Z is—CH₂CH₂CH₂—.

In some embodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein m is 1 and nis 1. In some embodiments is a compound of Formula (II), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein m is 2 and n is 1. In some embodiments is a compound of Formula(II), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, wherein m is 2 and n is 2. In some embodiments is a compound ofFormula (II), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein m is 3 and n is 1. In some embodiments isa compound of Formula (II), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein m is 3 and n is 2. In someembodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein m is 3 and nis 3.

In some embodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein a is 1, b is1, m is 2, and n is 2. In some embodiments is a compound of Formula(II), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, wherein a is 1, b is 2, m is 2, and n is 2. In some embodimentsis a compound of Formula (II), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein a is 1, b is 2, m is 1, and nis 2. In some embodiments is a compound of Formula (II), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein a is 1, b is 1, m is 1, and n is 2. In some embodiments is acompound of Formula (II), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein a is 2, b is 2, m is 1, and nis 2. In some embodiments is a compound of Formula (II), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein a is 2, b is 2, m is 1, and n is 1. In some embodiments is acompound of Formula (II), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein a is 2, b is 1, m is 1, and nis 1. In some embodiments is a compound of Formula (II), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein a is 1, b is 1, m is 1, and n is 1.

In some embodiments, provided herein is a compound of Formula (II), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein X is —O—. In some embodiments, provided herein is a compound ofFormula (II), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein X is —NH—. In some embodiments, providedherein is a compound of Formula (II), or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, wherein X is —N(R^(3a))—. Insome embodiments, provided herein is a compound of Formula (II), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein X is —S—. In some embodiments, provided herein is a compound ofFormula (II), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein X is —S(O)—. In some embodiments, providedherein is a compound of Formula (II), or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, wherein X is —S(O)₂—.

In some embodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein X is—N(R^(3a))— and R^(3a) is selected from C₁-C₆alkyl, —S(O)₂R¹⁰, —C(O)R¹⁰,and —C(O)OR¹¹. In some embodiments is a compound of Formula (II), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein X is —N(R^(3a))— and R^(3a) is selected from —S(O)₂R¹⁰,—C(O)R¹⁰, and —C(O)OR¹¹.

In some embodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein X is—N(R^(3a))— and R^(3a) is —S(O)₂R¹⁰. In some embodiments is a compoundof Formula (II), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein X is —N(R^(3a))—, R^(3a) is —S(O)₂R¹⁰, andR¹⁰ is C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkyl-O—C₁-C₆alkyl-,C₃-C₈cycloalkyl, C₂-C₉heterocyclyl, phenyl, or (phenyl)-C₁-C₆alkylene-.In some embodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein X is—N(R^(3a))—, R^(3a) is —S(O)₂R¹⁰, and R¹⁰ is C₁-C₆alkyl. In someembodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein X is—N(R^(3a))—, R^(3a) is —S(O)₂R¹⁰, and R¹⁰ is —CH₃. In some embodimentsis a compound of Formula (II), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein X is —N(R^(3a))—, R^(3a) is—S(O)₂R¹⁰, and R¹⁰ is —CH₂CH₃. In some embodiments is a compound ofFormula (II), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein X is —N(R^(3a))—, R^(3a) is —S(O)₂R¹⁰, andR¹⁰ is —CH₂CH₂CH₃. In some embodiments is a compound of Formula (II), ora pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein X is —N(R^(3a))—, R^(3a) is —S(O)₂R¹⁰, and R¹⁰ isC₁-C₆haloalkyl. In some embodiments is a compound of Formula (II), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein X is —N(R^(3a))—, R^(3a) is —S(O)₂R¹⁰, and R¹⁰ is —CF₃. In someembodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein X is—N(R^(3a))—, R^(3a) is —S(O)₂R¹⁰, and R¹⁰ is C₃-C₈cycloalkyl. In someembodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein X is—N(R^(3a))—, R^(3a) is —S(O)₂R¹⁰, and R¹⁰ is cyclopropyl.

In some embodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein X is—N(R^(3a))— and R^(3a) is —C(O)R¹⁰. In some embodiments is a compound ofFormula (II), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein X is —N(R^(3a))—, R^(3a) is —C(O)R¹⁰, andR¹⁰ is C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkyl-O—C₁-C₆alkyl-,C₃-C₈cycloalkyl, C₂-C₉heterocyclyl, phenyl, or (phenyl)-C₁-C₆alkylene-.In some embodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein X is—N(R^(3a))—, R^(3a) is —C(O)R¹⁰, and R¹⁰ is C₁-C₆alkyl. In someembodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein X is—N(R^(3a))—, R^(3a) is —C(O)R¹⁰, and R¹⁰ is —CH₃. In some embodiments isa compound of Formula (II), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein X is —N(R^(3a))—, R^(3a) is—C(O)R¹⁰, and R¹⁰ is —CH₂CH₃. In some embodiments is a compound ofFormula (II), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein X is —N(R^(3a))—, R^(3a) is —C(O)R¹⁰, andR¹⁰ is —CH₂CH₂CH₃. In some embodiments is a compound of Formula (II), ora pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein X is —N(R^(3a))—, R^(3a) is —C(O)R¹⁰, and R¹⁰ isC₁-C₆alkyl-O—C₁-C₆alkyl-. In some embodiments is a compound of Formula(II), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, wherein X is —N(R^(3a))—, R^(3a) is —C(O)R¹⁰, and R¹⁰ isC₃-C₈cycloalkyl. In some embodiments is a compound of Formula (II), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein X is —N(R^(3a))—, R^(3a) is —C(O)R¹⁰, and R¹⁰ isC₂-C₉heterocyclyl.

In some embodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein X is—N(R^(3a))— and R^(3a) is —C(O)OR¹¹. In some embodiments is a compoundof Formula (II), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein X is —N(R^(3a))—, R^(3a) is —C(O)OR¹¹, andR¹¹ is C₁-C₆alkyl. In some embodiments is a compound of Formula (II), ora pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein X is —N(R^(3a))—, R^(3a) is —C(O)OR¹¹, and R¹¹ is —CH₃. In someembodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein X is—N(R^(3a))—, R^(3a) is —C(O)OR¹¹, and R¹¹ is —CH₂CH₃. In someembodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein X is—N(R^(3a))—, R^(3a) is —C(O)OR¹¹, and R¹¹ is —CH₂CH₂CH₃.

In some embodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein p is 0, 1, 2,or 3. In some embodiments is a compound of Formula (II), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein p is 0. In some embodiments is a compound of Formula (II), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein p is 1. In some embodiments is a compound of Formula (II), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein p is 2. In some embodiments is a compound of Formula (II), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein p is 3. In some embodiments is a compound of Formula (II), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein p is 1, 2, or 3. In some embodiments is a compound of Formula(II), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, wherein p is 1, 2, or 3 and each R⁴ is independently halo,C₁-C₆alkyl, C₁-C₆alkenyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, orC₃-C₈cycloalkyl. In some embodiments is a compound of Formula (II), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein p is 1, 2, or 3 and each R⁴ is independently halo, C₁-C₆alkyl,or C₃-C₈cycloalkyl. In some embodiments is a compound of Formula (II),or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein p is 1 and R⁴ is halo, C₁-C₆alkyl, or C₃-C₈cycloalkyl. In someembodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein p is 2 andeach R⁴ is independently halo, C₁-C₆alkyl, or C₃-C₈cycloalkyl. In someembodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein p is 3 andeach R⁴ is independently halo, C₁-C₆alkyl, or C₃-C₈cycloalkyl.

In some embodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein q is 0, 1, 2,or 3. In some embodiments is a compound of Formula (II), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein q is 0. In some embodiments is a compound of Formula (II), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein q is 1. In some embodiments is a compound of Formula (II), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein q is 2. In some embodiments is a compound of Formula (II), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein q is 3. In some embodiments is a compound of Formula (II), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein q is 1, 2, or 3. In some embodiments is a compound of Formula(II), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, wherein q is 1, 2, or 3 and each R⁵ is independently halo,cyano, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, or C₃-C₈cycloalkyl. Insome embodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein q is 1, 2, or3 and each R⁵ is independently halo, cyano, C₁-C₆alkyl, C₁-C₆haloalkyl,or C₁-C₆alkoxy. In some embodiments is a compound of Formula (II), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein q is 1, 2, or 3 and each R⁵ is independently halo or C₁-C₆alkyl.In some embodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein q is 1 and R⁵is halo or C₁-C₆alkyl. In some embodiments is a compound of Formula(II), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, wherein q is 2 and each R⁵ is independently halo or C₁-C₆alkyl.In some embodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein q is 3 andeach R⁵ is independently halo or C₁-C₆alkyl.

In some embodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein k is 0, 1, 2,3, or 4. In some embodiments is a compound of Formula (II), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein k is 0, 1, 2, or 3. In some embodiments is a compound of Formula(II), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, wherein k is 0, 1, or 2. In some embodiments is a compound ofFormula (II), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein k is 0 or 1. In some embodiments is acompound of Formula (II), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein k is 0. In some embodiments isa compound of Formula (II), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein k is 1. In some embodiments isa compound of Formula (II), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein k is 1 and R³ is halo,C₁-C₆alkyl, or C₁-C₆haloalkyl. In some embodiments is a compound ofFormula (II), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein k is 2. In some embodiments is a compoundof Formula (II), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein k is 2 and each R³ is independently halo,C₁-C₆alkyl, or C₁-C₆haloalkyl.

In some embodiments, provided herein is a compound of Formula (IIa), ora pharmaceutically acceptable salt, solvate, or stereoisomer thereof:

wherein:

-   -   Z is —(C(R⁶)(R⁷))_(t)—;    -   each R³ is independently selected from halo and C₁-C₆alkyl;    -   R^(3a) is selected from C₁-C₆alkyl, C₁-C₆haloalkyl,        C₂-C₉heteroaryl, (C₂-C₉heteroaryl)-C₁-C₆alkylene-, oxo,        —S(O)₂R¹⁰, —C(O)R¹⁰, —C(O)OR¹¹, and —C(O)N(R¹)₂, wherein        C₂-C₉heteroaryl and (C₂-C₉heteroaryl)-C₁-C₆alkylene- are        optionally substituted with 1 to 3 groups independently selected        from halo, C₁-C₆alkyl, C₁-C₆haloalkyl, and hydroxyl;    -   each R⁴ and each R⁵ are each independently selected from halo,        cyano, —OH, C₁-C₆alkyl, C₁-C₆alkenyl, C₁-C₆haloalkyl,        C₁-C₆alkoxy, C₃-C₈cycloalkyl, —N(R⁹)₂, —C(O)R⁸, —C(O)OR⁹,        —C(O)N(R⁹)₂, —N(R⁹)C(O)R⁸, —N(R⁹)SO₂R⁸, —SO₂R⁸, and —SO₂N(R⁸)₂;    -   each R⁶ and each R⁷ are each independently hydrogen, halo, or        C₁-C₆alkyl;    -   each R⁸ is independently C₁-C₆alkyl or C₁-C₆haloalkyl;    -   each R⁹ is independently hydrogen, C₁-C₆alkyl, or        C₁-C₆haloalkyl;    -   R¹⁰ is C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkyl-O—C₁-C₆alkyl-,        C₃-C₈cycloalkyl, C₂-C₉heterocyclyl, phenyl,        (phenyl)-C₁-C₆alkylene-, C₂-C₉heteroaryl, or        (C₂-C₉heteroaryl)-C₁-C₆alkylene-, wherein the C₃-C₈cycloalkyl,        C₂-C₉heterocyclyl, phenyl, (phenyl)-C₁-C₆alkylene-,        C₂-C₉heteroaryl, or (C₂-C₉heteroaryl)-C₁-C₆alkylene- is        optionally substituted with 1 to 3 groups selected from halo,        C₁-C₆alkyl, C₁-C₆haloalkyl, and hydroxyl;    -   R¹¹ is independently hydrogen, C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   k is 0, 1, 2, 3, or 4;    -   p is 0, 1, 2, 3, or 4;    -   q is 0, 1, 2, 3 or 4; and    -   t is 0, 1, 2, or 3.

In some embodiments, provided herein is a compound of Formula (IIa), ora pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein each R⁶ and each R⁷ are each independently hydrogen orC₁-C₆alkyl. In some embodiments, provided herein is a compound ofFormula (IIa), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein each R⁶ and each R⁷ are hydrogen. In someembodiments, provided herein is a compound of Formula (IIa), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein each R⁶ and each R⁷ are each independently C₁-C₆alkyl. In someembodiments, provided herein is a compound of Formula (IIa), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein each R⁶ and each R⁷ are —CH₃. In some embodiments, providedherein is a compound of Formula (Ia), or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, wherein each R⁶ and each R⁷ areeach independently halo.

In some embodiments, provided herein is a compound of Formula (IIa), ora pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein t is 0. In some embodiments, provided herein is a compound ofFormula (IIa), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein t is 1, 2, or 3. In some embodiments,provided herein is a compound of Formula (IIa), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein t is 1. Insome embodiments, provided herein is a compound of Formula (IIa), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein t is 2. In some embodiments, provided herein is a compound ofFormula (IIa), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein t is 3.

In some embodiments, provided herein is a compound of Formula (IIa), ora pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein Z is —CH₂—. In some embodiments, provided herein is a compoundof Formula (IIa), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein Z is —CH₂CH₂—. In some embodiments,provided herein is a compound of Formula (IIa), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein Z is—CH₂CH₂CH₂—.

In some embodiments is a compound of Formula (IIa), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein R^(3a) is selected from C₁-C₆alkyl, C₂-C₉heteroaryl,(C₂-C₉heteroaryl)-C₁-C₆alkylene-, —S(O)₂R¹⁰, —C(O)R¹⁰, and —C(O)OR¹¹. Insome embodiments is a compound of Formula (IIa), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein R^(3a) isselected from C₁-C₆alkyl, —S(O)₂R¹⁰, —C(O)R¹⁰, and —C(O)OR¹¹. In someembodiments is a compound of Formula (IIa), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein R^(3a) isselected from —S(O)₂R¹⁰, —C(O)R¹⁰, and —C(O)OR¹¹.

In some embodiments is a compound of Formula (IIa), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein R^(3a) is —S(O)₂R¹⁰. In some embodiments is a compound ofFormula (IIa), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein R^(3a) is —S(O)₂R¹⁰ and R¹⁰ is C₁-C₆alkyl,C₁-C₆haloalkyl, C₁-C₆alkyl-O—C₁-C₆alkyl-, C₃-C₈cycloalkyl,C₂-C₉heterocyclyl, phenyl, or (phenyl)-C₁-C₆alkylene-. In someembodiments is a compound of Formula (IIa), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein R^(3a) is—S(O)₂R¹⁰ and R¹⁰ is C₁-C₆alkyl. In some embodiments is a compound ofFormula (IIa), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein R^(3a) is —S(O)₂R¹⁰ and R¹⁰ is —CH₃. Insome embodiments is a compound of Formula (IIa), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein R^(3a) is—S(O)₂R¹⁰ and R¹⁰ is —CH₂CH₃. In some embodiments is a compound ofFormula (IIa), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein R^(3a) is —S(O)₂R¹⁰ and R¹⁰ is —CH₂CH₂CH₃.

In some embodiments is a compound of Formula (IIa), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein R^(3a) is —S(O)₂R¹⁰ and R¹⁰ is C₁-C₆haloalkyl. In someembodiments is a compound of Formula (IIa), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein R^(3a) is—S(O)₂R¹⁰ and R¹⁰ is —CF₃. In some embodiments is a compound of Formula(IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, wherein R^(3a) is —S(O)₂R¹⁰ and R¹⁰ is C₃-C₈cycloalkyl.

In some embodiments is a compound of Formula (IIa), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein R^(3a) is —C(O)R¹⁰. In some embodiments is a compound of Formula(IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, wherein R^(3a) is —C(O)R¹⁰ and R¹⁰ is C₁-C₆alkyl,C₁-C₆haloalkyl, C₁-C₆alkyl-O—C₁-C₆alkyl-, C₃-C₈cycloalkyl,C₂-C₉heterocyclyl, phenyl, or (phenyl)-C₁-C₆alkylene-. In someembodiments is a compound of Formula (IIa), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein R^(3a) is—C(O)R¹⁰ and R¹⁰ is C₁-C₆alkyl. In some embodiments is a compound ofFormula (IIa), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein R^(3a) is —C(O)R¹⁰, and R¹⁰ is —CH₃. Insome embodiments is a compound of Formula (IIa), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein R^(3a) is—C(O)R¹⁰ and R¹⁰ is —CH₂CH₃. In some embodiments is a compound ofFormula (IIa), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein R^(3a) is —C(O)R¹⁰ and R¹⁰ is —CH₂CH₂CH₃.

In some embodiments is a compound of Formula (IIa), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein R^(3a) is —C(O)R¹⁰ and R¹⁰ is C₁-C₆alkyl-O—C₁-C₆alkyl-. In someembodiments is a compound of Formula (IIa), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein R^(3a) is—C(O)R¹⁰ and R¹⁰ is C₃-C₈cycloalkyl. In some embodiments is a compoundof Formula (IIa), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein R^(3a) is —C(O)R¹⁰ and R¹⁰ isC₂-C₉heterocyclyl.

In some embodiments is a compound of Formula (IIa), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein R^(3a) is —C(O)OR¹¹. In some embodiments is a compound ofFormula (IIa), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein R^(3a) is —C(O)OR¹¹ and R¹¹ is C₁-C₆alkyl.In some embodiments is a compound of Formula (IIa), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein R^(3a) is —C(O)OR¹¹ and R¹¹ is —CH₃. In some embodiments is acompound of Formula (IIa), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein R^(3a) is —C(O)OR¹¹ and R¹¹ is—CH₂CH₃. In some embodiments is a compound of Formula (IIa), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein R^(3a) is —C(O)OR¹¹ and R¹¹ is —CH₂CH₂CH₃.

In some embodiments is a compound of Formula (IIa), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein p is 0, 1, 2, or 3. In some embodiments is a compound of Formula(IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, wherein p is 0. In some embodiments is a compound of Formula(IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, wherein p is 1. In some embodiments is a compound of Formula(IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, wherein p is 2. In some embodiments is a compound of Formula(IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, wherein p is 3. In some embodiments is a compound of Formula(IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, wherein p is 1, 2, or 3. In some embodiments is a compound ofFormula (IIa), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein p is 1, 2, or 3 and each R⁴ isindependently halo, C₁-C₆alkyl, C₁-C₆alkenyl, C₁-C₆haloalkyl,C₁-C₆alkoxy, or C₃-C₈cycloalkyl. In some embodiments is a compound ofFormula (IIa), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein p is 1, 2, or 3 and each R⁴ isindependently halo, C₁-C₆alkyl, or C₃-C₈cycloalkyl. In some embodimentsis a compound of Formula (IIa), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein p is 1 and R⁴ is halo,C₁-C₆alkyl, or C₃-C₈cycloalkyl. In some embodiments is a compound ofFormula (IIa), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein p is 2 and each R⁴ is independently halo,C₁-C₆alkyl, or C₃-C₈cycloalkyl. In some embodiments is a compound ofFormula (IIa), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein p is 3 and each R⁴ is independently halo,C₁-C₆alkyl, or C₃-C₈cycloalkyl.

In some embodiments is a compound of Formula (IIa), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein q is 0, 1, 2, or 3. In some embodiments is a compound of Formula(IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, wherein q is 0. In some embodiments is a compound of Formula(IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, wherein q is 1. In some embodiments is a compound of Formula(IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, wherein q is 2. In some embodiments is a compound of Formula(IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, wherein q is 3. In some embodiments is a compound of Formula(IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, wherein q is 1, 2, or 3. In some embodiments is a compound ofFormula (IIa), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein q is 1, 2, or 3 and each R⁵ isindependently halo, cyano, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, orC₃-C₈cycloalkyl. In some embodiments is a compound of Formula (IIa), ora pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein q is 1, 2, or 3 and each R⁵ is independently halo, cyano,C₁-C₆alkyl, C₁-C₆haloalkyl, or C₁-C₆alkoxy. In some embodiments is acompound of Formula (IIa), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein q is 1, 2, or 3 and each R⁵ isindependently halo or C₁-C₆alkyl. In some embodiments is a compound ofFormula (IIa), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein q is 1 and R⁵ is halo or C₁-C₆alkyl. Insome embodiments is a compound of Formula (IIa), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein q is 2 andeach R⁵ is independently halo or C₁-C₆alkyl. In some embodiments is acompound of Formula (IIa), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein q is 3 and each R⁵ isindependently halo or C₁-C₆alkyl.

In some embodiments is a compound of Formula (IIa), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein k is 0, 1, 2, 3, or 4. In some embodiments is a compound ofFormula (IIa), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein k is 0, 1, 2, or 3. In some embodiments isa compound of Formula (IIa), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein k is 0, 1, or 2. In someembodiments is a compound of Formula (IIa), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein k is 0 or 1.In some embodiments is a compound of Formula (IIa), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein k is 0. In some embodiments is a compound of Formula (IIa), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein k is 1. In some embodiments is a compound of Formula (IIa), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein k is 1 and R³ is halo, C₁-C₆alkyl, or C₁-C₆haloalkyl. In someembodiments is a compound of Formula (IIa), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein k is 2. Insome embodiments is a compound of Formula (IIa), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein k is 2 andeach R³ is independently halo, C₁-C₆alkyl, or C₁-C₆haloalkyl.

In some embodiments, provided herein is a compound of Formula I selectedfrom:

-   2-(3′,6′-difluoro-2′-isopropyl-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;-   2-(3′,5′-difluoro-2′-isopropyl-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;-   2-(2′-ethyl-4′-((4-((methylsulfonyl)methyl)piperidin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;-   2-(2′-ethyl-4′-((4-(methylsulfonyl)piperidin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;-   6-((4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2-isopropyl-2′-methyl-[1,1′-biphenyl]-4-yl)methyl)-2-thia-6-azaspiro[3.4]octane    2,2-dioxide;-   6-((4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2-isopropyl-2′-methyl-[1,1′-biphenyl]-4-yl)methyl)-2-thia-6-azaspiro[3.3]heptane    2,2-dioxide;-   2-(2′-ethyl-4′-((6-(methylsulfonyl)-2-azaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;-   2-(2′-(sec-butyl)-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;-   2-(2′,3′-difluoro-6′-isopropyl-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;-   1,1,1,3,3,3-hexafluoro-2-(2′-fluoro-6′-isopropyl-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)propan-2-ol;-   6-((2-ethyl-4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2′-methyl-[1,1′-biphenyl]-4-yl)methyl)-2-thia-6-azaspiro[3.4]octane    2,2-dioxide;-   6-((2-ethyl-4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1′-biphenyl]-4-yl)methyl)-2-thia-6-azaspiro[3.4]octane    2,2-dioxide;-   6-((2-ethyl-4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2′-methyl-[1,1′-biphenyl]-4-yl)methyl)-2-thia-6-azaspiro[3.3]heptane    2,2-dioxide;-   2-(2′-ethyl-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.5]nonan-2-yl)methyl)-[11,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;-   2-(2′-ethyl-4′-((2-(methylsulfonyl)-2,6-diazaspiro[3.5]nonan-6-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;-   2-(2′-ethyl-4′-((6-(isobutylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;-   2-(2′-ethyl-4′-((6-(propylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;-   2-(2′-ethyl-4′-((6-(ethylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;-   2-((2-ethyl-4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1′-biphenyl]-4-yl)methyl)-7-thia-2-azaspiro[3.5]nonane    7,7-dioxide;-   2-(2′-(tert-butyl)-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;-   2-((2-ethyl-4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1′-biphenyl]-4-yl)methyl)-6-thia-2-azaspiro[3.4]octane    6,6-dioxide;-   2-((2-ethyl-4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1′-biphenyl]-4-yl)methyl)-6-thia-2-azaspiro[3.4]octane    6-oxide;-   6-((2-ethyl-4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1′-biphenyl]-4-yl)methyl)-2-thia-6-azaspiro[3.3]heptane    2,2-dioxide;-   6-((2-ethyl-4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1′-biphenyl]-4-yl)methyl)-2-thia-6-azaspiro[3.3]heptane    2-oxide;-   2-(4′-((2-thia-6-azaspiro[3.3]heptan-6-yl)methyl)-2′-ethyl-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;-   N-((1-((2-ethyl-4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1′-biphenyl]-4-yl)methyl)azetidin-3-yl)methyl)-N-methylmethanesulfonamide;-   2-(2′-ethyl-4′-((2-(methylsulfonyl)-2,6-diazaspiro[3.4]octan-6-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;-   2-(2′-ethyl-4′-((7-(methylsulfonyl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;-   N-((1-((2-ethyl-4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1′-biphenyl]-4-yl)methyl)azetidin-3-yl)methyl)methanesulfonamide;-   2-(2′-ethyl-4′-((7-(methylsulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;-   2-(2′-ethyl-4′-((2-(methylsulfonyl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;-   2-(2′-ethyl-2-fluoro-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;-   2-(2′-ethyl-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.4]octan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;-   2-(2′-ethyl-6′-fluoro-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;-   2-(2′-ethyl-5′-fluoro-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;-   2-(2′-ethyl-3′-fluoro-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;-   tert-butyl    2-((2-ethyl-4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1′-biphenyl]-4-yl)methyl)-2,6-diazaspiro[3.4]octane-6-carboxylate;-   2-(2′-ethyl-2-methyl-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;-   methyl    6-((2-ethyl-4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1′-biphenyl]-4-yl)methyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate;-   2-(4′-((6-(cyclopropylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-2′-ethyl-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;-   2-(2′-cyclopropyl-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;-   1,1,1,3,3,3-hexafluoro-2-(2′-isopropyl-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)propan-2-ol;-   tert-butyl    6-((2-ethyl-4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1′-biphenyl]-4-yl)methyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate;-   1,1,1,3,3,3-hexafluoro-2-(4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-2′-(prop-1-en-2-yl)-[1,1′-biphenyl]-4-yl)propan-2-ol;-   2-(2′-bromo-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;-   1,1,1,3,3,3-hexafluoro-2-(4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-2′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)propan-2-ol;-   2-(2′-chloro-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;-   1-(6-((2-ethyl-4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1′-biphenyl]-4-yl)methyl)-2,6-diazaspiro[3.3]heptan-2-yl)ethan-1-one;-   2-(2′-ethyl-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;-   1-(6-((4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2-methyl-[1,1′-biphenyl]-4-yl)methyl)-2,6-diazaspiro[3.3]heptan-2-yl)ethan-1-one;-   1,1,1,3,3,3-hexafluoro-2-(2′-methyl-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)propan-2-ol;-   1,1,1,3,3,3-hexafluoro-2-(2′-methyl-4′-((6-(pyridin-4-ylmethyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)propan-2-ol;-   2-(4-(3-ethyl-5-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)pyridin-2-yl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol;-   7-((2-ethyl-4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1′-biphenyl]-4-yl)methyl)-2,7-diazaspiro[4.4]nonan-1-one;-   7-((2-ethyl-4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1′-biphenyl]-4-yl)methyl)-2,7-diazaspiro[4.4]nonan-3-one;-   4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-N,N-dimethyl-4-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-2-carboxamide;-   2-(2′-ethyl-2-methoxy-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;-   1,1,1,3,3,3-hexafluoro-2-(2′-methoxy-2-methyl-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)propan-2-ol;-   7-((2-ethyl-4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1′-biphenyl]-4-yl)methyl)-2-thia-7-azaspiro[4.4]nonane    2,2-dioxide;-   2-(5-(2-ethyl-4-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)phenyl)pyridin-2-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;-   2-(4-(4-ethyl-6-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)pyridin-3-yl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol;-   4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-4-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-3-ol;-   2-2-cyclopropyl-3′,6′-difluoro-4-(((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;-   2-(2′-cyclopropyl-2,3′,6′-trifluoro-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;-   2-(2-chloro-2′-cyclopropyl-3′,6′-difluoro-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;-   1,1,1,3,3,3-hexafluoro-2-(2,3′,6′-trifluoro-2′-isopropyl-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)propan-2-ol;-   2-(2′-cyclopropyl-2-ethyl-3′,6′-difluoro-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;-   2-(2′-cyclopropyl-3′,6′-difluoro-2-methyl-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;-   2-(2-chloro-5′-fluoro-2′-isopropyl-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;-   1,1,1,3,3,3-hexafluoro-2-(5′-fluoro-2′-isopropyl-2-methyl-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)propan-2-ol;-   2-(2,5′-difluoro-2′-isopropyl-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;-   2-(2-chloro-3′,6′-difluoro-2′-isopropyl-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;-   2-(2-ethyl-3′,6′-difluoro-2′-isopropyl-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;-   2-(3′,6′-difluoro-2′-isopropyl-2-methyl-4′-((6-(methylsulfonyl-   2-(2′-ethyl-3′,6′-difluoro-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;-   2-(2,2′-diethyl-3′,6′-difluoro-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;-   2-(2-chloro-2′-ethyl-3′,6′-difluoro-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;-   2-(2-chloro-2′-ethyl-5′-fluoro-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;-   2-(2′-ethyl-2,5′-difluoro-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;-   1,1,1,3,3,3-hexafluoro-2-(5′-fluoro-2′-isopropyl-4′-(((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)propan-2-ol;-   2-(2,2′-diethyl-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;-   2-(2′-ethyl-2,3′,6′-trifluoro-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;-   2-(2-ethyl-2′-methyl-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;-   2-(2-chloro-2′-ethyl-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;-   2-(3′,6′-difluoro-2′-isopropyl-4′-((2-(methylsulfonyl)-2,6-diazaspiro[3.4]octan-6-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;-   2-(4-(2-ethyl-6-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)pyridin-3-yl)-3-methylphenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol;-   2-(2′-ethyl-3′,6′-difluoro-2-methyl-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;-   2′-ethyl-4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-2-carbonitrile;-   2-(4-(4-ethyl-6-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)pyridin-3-yl)-3-methylphenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol;-   2-(6-(2-ethyl-4-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)phenyl)pyridin-3-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;-   2-(4-(3-ethyl-5-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)pyridin-2-yl)-3-methylphenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol;-   1,1,1,3,3,3-hexafluoro-2-(3-methyl-4-(6-(6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)phenyl)propan-2-ol;    and-   2-(2,2′-dimethyl-3′-(6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;    or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments, the compounds provided herein were found to haveIC₅₀s of about or less than 50 nM in the RORγ Gal4 ligand binding assay.In some embodiments, the compounds provided herein were found to haveIC₅₀s of about or less than 100 nM in the RORγ Gal4 ligand bindingassay. In some embodiments, the compounds provided herein have IC₅₀s ofabout 10 nM or less, about 20 nM or less, about 25 nM or less, about 50nM or less, about 100 nM or less, about 250 nM or less, or about 500 nMor less in the RORγ Gal4 ligand binding assay. In another embodiment,the compounds provided herein modulate RORγ selectively over RORalpha.

Any combination of the groups described above for the various variablesis contemplated herein. Throughout the specification, groups andsubstituents thereof can be chosen by one skilled in the field toprovide stable moieties and compounds.

In some embodiments, the compound described herein is present in thepharmaceutical composition as a pharmaceutically acceptable salt. Insome embodiments, any compound described above is suitable for anymethod or composition described herein.

In certain embodiments, the compounds presented herein possess one ormore stereocenters and each center independently exists in either the Ror S configuration. The compounds presented herein include alldiastereomeric, enantiomeric, and epimeric forms as well as theappropriate mixtures thereof. Stereoisomers are obtained, if desired, bymethods such as, stereoselective synthesis and/or the separation ofstereoisomers by chiral chromatographic columns.

In some embodiments, a compound of Formula (I), (Ia), (Ib), (II), or(IIa) is used as a single enantiomer. In some embodiments, a compound ofFormula (I), (Ia), (Ib), (II), or (IIa) is used as a racemic mixture.

The methods and formulations described herein include the use ofN-oxides (if appropriate), or pharmaceutically acceptable salts ofcompounds having the structures presented herein, as well as activemetabolites of these compounds having the same type of activity. In somesituations, compounds may exist as tautomers. All tautomers are includedwithin the scope of the compounds presented herein. In specificembodiments, the compounds described herein exist in solvated forms withpharmaceutically acceptable solvents such as water, ethanol, and thelike. In other embodiments, the compounds described herein exist inunsolvated form.

In some embodiments, the compounds of Formula (I), (Ia), (Ib), (II), or(IIa) described herein include solvent addition forms thereof. Solvatescontain either stoichiometric or non-stoichiometric amounts of a solventwith pharmaceutically acceptable solvents such as water, ethanol, andthe like. Hydrates are formed when the solvent is water, or alcoholatesare formed when the solvent is alcohol.

In some embodiments, sites on the compounds of Formula (I), (Ia), (Ib),(II), or (IIa) disclosed herein are susceptible to various metabolicreactions. Therefore incorporation of appropriate substituents at theplaces of metabolic reactions will reduce, minimize or eliminate themetabolic pathways. In specific embodiments, the appropriate substituentto decrease or eliminate the susceptibility of the aromatic ring tometabolic reactions is, by way of example only, a halogen, deuterium oran alkyl group.

In some embodiments, the compounds of Formula (I), (Ia), (Ib), (II), or(IIa) disclosed herein are isotopically-labeled, which are identical tothose recited in the various formulae and structures presented herein,but for the fact that one or more atoms are replaced by an atom havingan atomic mass or mass number different from the atomic mass or massnumber usually found in nature. In some embodiments, one or morehydrogen atoms are replaced with deuterium. In some embodiments,metabolic sites on the compounds described herein are deuterated. Insome embodiments, substitution with deuterium affords certaintherapeutic advantages resulting from greater metabolic stability, suchas, for example, increased in vivo half-life or reduced dosagerequirements and thus decreasing toxicity or lowering the probability ofdrug-drug interactions.

Synthesis of Compounds

In some embodiments, the synthesis of compounds described herein areaccomplished using means described in the chemical literature, using themethods described herein, or by a combination thereof. In addition,solvents, temperatures and other reaction conditions presented hereinmay vary.

In other embodiments, the starting materials and reagents used for thesynthesis of the compounds described herein are synthesized or areobtained from commercial sources, such as, but not limited to,Sigma-Aldrich, FischerScientific (Fischer Chemicals), and AcrosOrganics.

In further embodiments, the compounds described herein, and otherrelated compounds having different substituents are synthesized usingtechniques and materials described herein as well as those that arerecognized in the field, such as described, for example, in Fieser andFieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley andSons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 andSupplementals (Elsevier Science Publishers, 1989); Organic Reactions,Volumes 1-40 (John Wiley and Sons, 1991), Larock's Comprehensive OrganicTransformations (VCH Publishers Inc., 1989), March, Advanced OrganicChemistry 4^(th) Ed., (Wiley 1992); Carey and Sundberg, Advanced OrganicChemistry 4^(th) Ed., Vols. A and B (Plenum 2000, 2001), and Green andWuts, Protective Groups in Organic Synthesis 3^(rd) Ed., (Wiley 1999)(all of which are incorporated by reference for such disclosure).General methods for the preparation of compound as disclosed herein maybe derived from reactions and the reactions may be modified by the useof appropriate reagents and conditions, for the introduction of thevarious moieties found in the formulae as provided herein. As a guidethe following synthetic methods may be utilized.

Use of Protecting Groups

In the reactions described, it may be necessary to protect reactivefunctional groups, for example hydroxy, amino, imino, thio or carboxygroups, where these are desired in the final product, in order to avoidtheir unwanted participation in reactions. Protecting groups are used toblock some or all of the reactive moieties and prevent such groups fromparticipating in chemical reactions until the protective group isremoved. It is preferred that each protective group be removable by adifferent means. Protective groups that are cleaved under totallydisparate reaction conditions fulfill the requirement of differentialremoval.

Protective groups can be removed by acid, base, reducing conditions(such as, for example, hydrogenolysis), and/or oxidative conditions.Groups such as trityl, dimethoxytrityl, acetal and t-butyldimethylsilylare acid labile and may be used to protect carboxy and hydroxy reactivemoieties in the presence of amino groups protected with Cbz groups,which are removable by hydrogenolysis, and Fmoc groups, which are baselabile. Carboxylic acid and hydroxy reactive moieties may be blockedwith base labile groups such as, but not limited to, methyl, ethyl, andacetyl in the presence of amines blocked with acid labile groups such ast-butyl carbamate or with carbamates that are both acid and base stablebut hydrolytically removable.

Carboxylic acid and hydroxy reactive moieties may also be blocked withhydrolytically removable protective groups such as the benzyl group,while amine groups capable of hydrogen bonding with acids may be blockedwith base labile groups such as Fmoc. Carboxylic acid reactive moietiesmay be protected by conversion to simple ester compounds as exemplifiedherein, which include conversion to alkyl esters, or they may be blockedwith oxidatively-removable protective groups such as2,4-dimethoxybenzyl, while co-existing amino groups may be blocked withfluoride labile silyl carbamates.

Allyl blocking groups are useful in the presence of acid- andbase-protecting groups since the former are stable and can besubsequently removed by metal or pi-acid catalysts. For example, anallyl-blocked carboxylic acid can be deprotected with a Pd⁰-catalyzedreaction in the presence of acid labile t-butyl carbamate or base-labileacetate amine protecting groups. Yet another form of protecting group isa resin to which a compound or intermediate may be attached. As long asthe residue is attached to the resin, that functional group is blockedand cannot react. Once released from the resin, the functional group isavailable to react.

Typically blocking/protecting groups may be selected from:

Other protecting groups, plus a detailed description of techniquesapplicable to the creation of protecting groups and their removal aredescribed in Greene and Wuts, Protective Groups in Organic Synthesis,3rd Ed., John Wiley & Sons, New York, N.Y., 1999, and Kocienski,Protective Groups, Thieme Verlag, New York, N.Y., 1994, which areincorporated herein by reference for such disclosure).

Methods of Treatment and Prevention

In one embodiment, provided herein are methods for modulating of RORγactivity in a cell by contacting the cell with an RORγ modulator.Examples of such RORγ modulators are described above.

In some embodiments is a method of treating a disease, disorder, orcondition in an individual in need thereof comprising administering tothe individual a therapeutically effective amount of a compound ofFormula (I), (Ia), (Ib), (II), or (IIa), or a pharmaceuticallyacceptable salt or solvate thereof, wherein the disease, disorder, orcondition is selected from psoriasis, psoriatic arthritis, uveitis,ulcerative colitis, asthma, allergic rhinitis, chronic obstructivepulmonary disease (COPD), atopic dermatitis, vitiligo, vesiculobullousdermatosis, rheumatoid arthritis, ankylosing spondylitis, reactivearthritis, arthritis associated with inflammatory bowel disease,juvenile rheumatoid arthritis, Crohn's disease, inflammatory boweldisease, lupus, lupus nephritis, multiple sclerosis, axialspodyloarthritides, hidraenitis suppurativa, Sjögren's syndrome,regional enteritis, Tolosa-Hunt syndrome, undifferentiated connectivetissue disease, obesity, obesity-induced insulin resistance,atherosclerosis, and type II diabetes. In some embodiments is a methodof treating a disease, disorder or condition in an individual in needthereof comprising administering to the individual a therapeuticallyeffective amount of a compound of Formula (I), (Ia), (Ib), (II), or(IIa), or a pharmaceutically acceptable salt or solvate thereof, whereinthe disease, disorder, or condition is psoriasis. In some embodiments isa method of treating a disease, disorder or condition in an individualin need thereof comprising administering to the individual atherapeutically effective amount of a compound of Formula (I), (Ia),(Ib), (II), or (IIa), or a pharmaceutically acceptable salt or solvatethereof, wherein the disease, disorder, or condition is psoriaticarthritis. In some embodiments is a method of treating a disease,disorder or condition in an individual in need thereof comprisingadministering to the individual a therapeutically effective amount of acompound of Formula (I), (Ia), (Ib), (II), or (IIa), or apharmaceutically acceptable salt or solvate thereof, wherein thedisease, disorder, or condition is uveitis. In some embodiments is amethod of treating a disease, disorder or condition in an individual inneed thereof comprising administering to the individual atherapeutically effective amount of a compound of Formula (I), (Ia),(Ib), (II), or (IIa), or a pharmaceutically acceptable salt or solvatethereof, wherein the disease, disorder, or condition is ulcerativecolitis. In some embodiments is a method of treating a disease, disorderor condition in an individual in need thereof comprising administeringto the individual a therapeutically effective amount of a compound ofFormula (I), (Ia), (Ib), (II), or (IIa), or a pharmaceuticallyacceptable salt or solvate thereof, wherein the disease, disorder, orcondition is asthma. In some embodiments is a method of treating adisease, disorder or condition in an individual in need thereofcomprising administering to the individual a therapeutically effectiveamount of a compound of Formula (I), (Ia), (Ib), (II), or (IIa), or apharmaceutically acceptable salt or solvate thereof, wherein thedisease, disorder, or condition is allergic rhinitis. In someembodiments is a method of treating a disease, disorder or condition inan individual in need thereof comprising administering to the individuala therapeutically effective amount of a compound of Formula (I), (Ia),(Ib), (II), or (IIa), or a pharmaceutically acceptable salt or solvatethereof, wherein the disease, disorder, or condition is chronicobstructive pulmonary disease (COPD). In some embodiments is a method oftreating a disease, disorder or condition in an individual in needthereof comprising administering to the individual a therapeuticallyeffective amount of a compound of Formula (I), (Ia), (Ib), (II), or(IIa), or a pharmaceutically acceptable salt or solvate thereof, whereinthe disease, disorder, or condition is atopic dermatitis. In someembodiments is a method of treating a disease, disorder or condition inan individual in need thereof comprising administering to the individuala therapeutically effective amount of a compound of Formula (I), (Ia),(Ib), (II), or (IIa), or a pharmaceutically acceptable salt or solvatethereof, wherein the disease, disorder, or condition is vitiligo. Insome embodiments is a method of treating a disease, disorder orcondition in an individual in need thereof comprising administering tothe individual a therapeutically effective amount of a compound ofFormula (I), (Ia), (Ib), (II), or (IIa), or a pharmaceuticallyacceptable salt or solvate thereof, wherein the disease, disorder, orcondition is vesiculobullous dermatosis. In some embodiments is a methodof treating a disease, disorder or condition in an individual in needthereof comprising administering to the individual a therapeuticallyeffective amount of a compound of Formula (I), (Ia), (Ib), (II), or(IIa), or a pharmaceutically acceptable salt or solvate thereof, whereinthe disease, disorder, or condition is rheumatoid arthritis. In someembodiments is a method of treating a disease, disorder or condition inan individual in need thereof comprising administering to the individuala therapeutically effective amount of a compound of Formula (I), (Ia),(Ib), (II), or (IIa), or a pharmaceutically acceptable salt or solvatethereof, wherein the disease, disorder, or condition is ankylosingspondylitis. In some embodiments is a method of treating a disease,disorder or condition in an individual in need thereof comprisingadministering to the individual a therapeutically effective amount of acompound of Formula (I), (Ia), (Ib), (II), or (IIa), or apharmaceutically acceptable salt or solvate thereof, wherein thedisease, disorder, or condition is reactive arthritis. In someembodiments is a method of treating a disease, disorder or condition inan individual in need thereof comprising administering to the individuala therapeutically effective amount of a compound of Formula (I), (Ia),(Ib), (II), or (IIa), or a pharmaceutically acceptable salt or solvatethereof, wherein the disease, disorder, or condition is arthritisassociated with inflammatory bowel disease. In some embodiments is amethod of treating a disease, disorder or condition in an individual inneed thereof comprising administering to the individual atherapeutically effective amount of a compound of Formula (I), (Ia),(Ib), (II), or (IIa), or a pharmaceutically acceptable salt or solvatethereof, wherein the disease, disorder, or condition is juvenilerheumatoid arthritis. In some embodiments is a method of treating adisease, disorder or condition in an individual in need thereofcomprising administering to the individual a therapeutically effectiveamount of a compound of Formula (I), (Ia), (Ib), (II), or (IIa), or apharmaceutically acceptable salt or solvate thereof, wherein thedisease, disorder, or condition is Crohn's disease. In some embodimentsis a method of treating a disease, disorder or condition in anindividual in need thereof comprising administering to the individual atherapeutically effective amount of a compound of Formula (I), (Ia),(Ib), (II), or (IIa), or a pharmaceutically acceptable salt or solvatethereof, wherein the disease, disorder, or condition is inflammatorybowel disease. In some embodiments is a method of treating a disease,disorder or condition in an individual in need thereof comprisingadministering to the individual a therapeutically effective amount of acompound of Formula (I), (Ia), (Ib), (II), or (IIa), or apharmaceutically acceptable salt or solvate thereof, wherein thedisease, disorder, or condition is lupus. In some embodiments is amethod of treating a disease, disorder or condition in an individual inneed thereof comprising administering to the individual atherapeutically effective amount of a compound of Formula (I), (Ia),(Ib), (II), or (IIa), or a pharmaceutically acceptable salt or solvatethereof, wherein the disease, disorder, or condition is lupus nephritis.In some embodiments is a method of treating a disease, disorder orcondition in an individual in need thereof comprising administering tothe individual a therapeutically effective amount of a compound ofFormula (I), (Ia), (Ib), (II), or (IIa), or a pharmaceuticallyacceptable salt or solvate thereof, wherein the disease, disorder, orcondition is multiple sclerosis. In some embodiments is a method oftreating a disease, disorder or condition in an individual in needthereof comprising administering to the individual a therapeuticallyeffective amount of a compound of Formula (I), (Ia), (Ib), (II), or(IIa), or a pharmaceutically acceptable salt or solvate thereof, whereinthe disease, disorder, or condition is axial spodyloarthritides. In someembodiments is a method of treating a disease, disorder or condition inan individual in need thereof comprising administering to the individuala therapeutically effective amount of a compound of Formula (I), (Ia),(Ib), (II), or (IIa), or a pharmaceutically acceptable salt or solvatethereof, wherein the disease, disorder, or condition is hidraenitissuppurativa. In some embodiments is a method of treating a disease,disorder or condition in an individual in need thereof comprisingadministering to the individual a therapeutically effective amount of acompound of Formula (I), (Ia), (Ib), (II), or (IIa), or apharmaceutically acceptable salt or solvate thereof, wherein thedisease, disorder, or condition is Sjögren's syndrome. In someembodiments is a method of treating a disease, disorder or condition inan individual in need thereof comprising administering to the individuala therapeutically effective amount of a compound of Formula (I), (Ia),(Ib), (II), or (IIa), or a pharmaceutically acceptable salt or solvatethereof, wherein the disease, disorder, or condition is regionalenteritis. In some embodiments is a method of treating a disease,disorder or condition in an individual in need thereof comprisingadministering to the individual a therapeutically effective amount of acompound of Formula (I), (Ia), (Ib), (II), or (IIa), or apharmaceutically acceptable salt or solvate thereof, wherein thedisease, disorder, or condition is Tolosa-Hunt syndrome. In someembodiments is a method of treating a disease, disorder or condition inan individual in need thereof comprising administering to the individuala therapeutically effective amount of a compound of Formula (I), (Ia),(Ib), (II), or (IIa), or a pharmaceutically acceptable salt or solvatethereof, wherein the disease, disorder, or condition is undifferentiatedconnective tissue disease. In some embodiments is a method of treating adisease, disorder or condition in an individual in need thereofcomprising administering to the individual a therapeutically effectiveamount of a compound of Formula (I), (Ia), (Ib), (II), or (IIa), or apharmaceutically acceptable salt or solvate thereof, wherein thedisease, disorder, or condition is obesity. In some embodiments is amethod of treating a disease, disorder or condition in an individual inneed thereof comprising administering to the individual atherapeutically effective amount of a compound of Formula (I), (Ia),(Ib), (II), or (IIa), or a pharmaceutically acceptable salt or solvatethereof, wherein the disease, disorder, or condition is obesity-inducedinsulin resistance. In some embodiments is a method of treating adisease, disorder or condition in an individual in need thereofcomprising administering to the individual a therapeutically effectiveamount of a compound of Formula (I), (Ia), (Ib), (II), or (IIa), or apharmaceutically acceptable salt or solvate thereof, wherein thedisease, disorder, or condition is atherosclerosis. In some embodimentsis a method of treating a disease, disorder or condition in anindividual in need thereof comprising administering to the individual atherapeutically effective amount of a compound of Formula (I), (Ia),(Ib), (II), or (IIa), or a pharmaceutically acceptable salt or solvatethereof, wherein the disease, disorder, or condition is type IIdiabetes.

Pharmaceutical Compositions and Methods of Administration of RORγModulators

RORγ modulators described herein are administered to subjects in abiologically compatible form suitable for administration to treat orprevent diseases, disorders or conditions. Administration of RORγmodulators as described herein can be in any pharmacological formincluding a therapeutically effective amount of an RORγ modulator aloneor in combination with a pharmaceutically acceptable carrier.

In certain embodiments, the compounds described herein are administeredas a pure chemical. In other embodiments, the compounds described hereinare combined with a pharmaceutically suitable or acceptable carrier(also referred to herein as a pharmaceutically suitable (or acceptable)excipient, physiologically suitable (or acceptable) excipient, orphysiologically suitable (or acceptable) carrier) selected on the basisof a chosen route of administration and standard pharmaceutical practiceas described, for example, in Remington: The Science and Practice ofPharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, Pa. (2005)).

Accordingly, provided herein is a pharmaceutical composition comprisingat least one compound described herein, or a pharmaceutically acceptablesalt, together with one or more pharmaceutically acceptable carriers.The carrier(s) (or excipient(s)) is acceptable or suitable if thecarrier is compatible with the other ingredients of the composition andnot deleterious to the recipient (i.e., the subject) of the composition.

In some embodiments is a pharmaceutical composition comprising apharmaceutically acceptable carrier and a compound of Formula (I), (Ia),(Ib), (II), or (IIa), or a pharmaceutically acceptable salt or solvatethereof. In some embodiments is a pharmaceutical composition comprisinga pharmaceutically acceptable carrier and a compound of Formula (I), ora pharmaceutically acceptable salt or solvate thereof. In someembodiments is a pharmaceutical composition comprising apharmaceutically acceptable carrier and a compound of Formula (Ia), or apharmaceutically acceptable salt or solvate thereof. In some embodimentsis a pharmaceutical composition comprising a pharmaceutically acceptablecarrier and a compound of Formula (Ib), or a pharmaceutically acceptablesalt or solvate thereof. In some embodiments is a pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and acompound of Formula (II), or a pharmaceutically acceptable salt orsolvate thereof. In some embodiments is a pharmaceutical compositioncomprising a pharmaceutically acceptable carrier and a compound ofFormula (IIa), or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments is a pharmaceutical composition consistingessentially of a pharmaceutically acceptable carrier and a compound ofFormula (I), (Ia), (Ib), (II), or (IIa), or a pharmaceuticallyacceptable salt thereof. In some embodiments is a pharmaceuticalcomposition consisting essentially of a pharmaceutically acceptablecarrier and a compound of Formula (I), or a pharmaceutically acceptablesalt or solvate thereof. In some embodiments is a pharmaceuticalcomposition consisting essentially of a pharmaceutically acceptablecarrier and a compound of Formula (Ia), or a pharmaceutically acceptablesalt or solvate thereof. In some embodiments is a pharmaceuticalcomposition consisting essentially of a pharmaceutically acceptablecarrier and a compound of Formula (Ib), or a pharmaceutically acceptablesalt or solvate thereof. In some embodiments is a pharmaceuticalcomposition consisting essentially of a pharmaceutically acceptablecarrier and a compound of Formula (II), or a pharmaceutically acceptablesalt or solvate thereof. In some embodiments is a pharmaceuticalcomposition consisting essentially of a pharmaceutically acceptablecarrier and a compound of Formula (IIa), or a pharmaceuticallyacceptable salt or solvate thereof.

In certain embodiments, the compound as described herein issubstantially pure, in that it contains less than about 5%, or less thanabout 1%, or less than about 0.1%, of other organic small molecules,such as contaminating intermediates or by-products that are created, forexample, in one or more of the steps of a synthesis method.

These formulations include those suitable for oral, topical, buccal,parenteral (e.g., subcutaneous, intramuscular, intradermal, orintravenous), or aerosol administration.

Exemplary pharmaceutical compositions are used in the form of apharmaceutical preparation, for example, in solid, semisolid or liquidform, which includes one or more of a disclosed compound, as an activeingredient, in a mixture with an organic or inorganic carrier orexcipient suitable for external, enteral or parenteral applications. Insome embodiments, the active ingredient is compounded, for example, withthe usual non-toxic, pharmaceutically acceptable carriers for tablets,pellets, capsules, suppositories, solutions, emulsions, suspensions, andany other form suitable for use. The active object compound is includedin the pharmaceutical composition in an amount sufficient to produce thedesired effect upon the process or condition of the disease.

In some embodiments for preparing solid compositions such as tablets,the principal active ingredient is mixed with a pharmaceutical carrier,e.g., conventional tableting ingredients such as corn starch, lactose,sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalciumphosphate or gums, and other pharmaceutical diluents, e.g., water, toform a solid preformulation composition containing a homogeneous mixtureof a disclosed compound or a non-toxic pharmaceutically acceptable saltthereof. When referring to these preformulation compositions ashomogeneous, it is meant that the active ingredient is dispersed evenlythroughout the composition so that the composition is readily subdividedinto equally effective unit dosage forms such as tablets, pills andcapsules.

In solid dosage forms for oral administration (capsules, tablets, pills,dragees, powders, granules and the like), the subject composition ismixed with one or more pharmaceutically acceptable carriers, such assodium citrate or dicalcium phosphate, and/or any of the following: (1)fillers or extenders, such as starches, cellulose, microcrystallinecellulose, silicified microcrystalline cellulose, lactose, sucrose,glucose, mannitol, and/or silicic acid; (2) binders, such as, forexample, carboxymethylcellulose, hypromellose, alginates, gelatin,polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such asglycerol; (4) disintegrating agents, such as crospovidone,croscarmellose sodium, sodium starch glycolate, agar-agar, calciumcarbonate, potato or tapioca starch, alginic acid, certain silicates,and sodium carbonate; (5) solution retarding agents, such as paraffin;(6) absorption accelerators, such as quaternary ammonium compounds; (7)wetting agents, such as, for example, docusate sodium, cetyl alcohol andglycerol monostearate; (8) absorbents, such as kaolin and bentoniteclay; (9) lubricants, such a talc, calcium stearate, magnesium stearate,solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof;and (10) coloring agents.

In the case of capsules, tablets and pills, in some embodiments, thecompositions comprise buffering agents. In some embodiments, solidcompositions of a similar type are also employed as fillers in soft andhard-filled gelatin capsules using such excipients as lactose or milksugars, as well as high molecular weight polyethylene glycols and thelike.

In some embodiments, a tablet is made by compression or molding,optionally with one or more accessory ingredients. In some embodiments,compressed tablets are prepared using binder (for example, gelatin orhydroxypropylmethyl cellulose), lubricant, inert diluent, preservative,disintegrant (for example, sodium starch glycolate or cross-linkedsodium carboxymethyl cellulose), surface-active or dispersing agent. Insome embodiments, molded tablets are made by molding in a suitablemachine a mixture of the subject composition moistened with an inertliquid diluent. In some embodiments, tablets, and other solid dosageforms, such as dragees, capsules, pills and granules, are scored orprepared with coatings and shells, such as enteric coatings and othercoatings.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. Liquid dosage forms for oraladministration include pharmaceutically acceptable emulsions,microemulsions, solutions, suspensions, syrups and elixirs. In additionto the subject composition, in some embodiments, the liquid dosage formscontain inert diluents, such as, for example, water or other solvents,solubilizing agents and emulsifiers, such as ethyl alcohol, isopropylalcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzylbenzoate, propylene glycol, 1,3-butylene glycol, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor and sesame oils),glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acidesters of sorbitan, cyclodextrins and mixtures thereof.

In some embodiments, suspensions, in addition to the subjectcomposition, contain suspending agents as, for example, ethoxylatedisostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters,microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agarand tragacanth, and mixtures thereof.

In some embodiments, powders and sprays contain, in addition to asubject composition, excipients such as lactose, talc, silicic acid,aluminum hydroxide, calcium silicates and polyamide powder, or mixturesof these substances. In some embodiments, sprays additionally containcustomary propellants, such as chlorofluorohydrocarbons and volatileunsubstituted hydrocarbons, such as butane and propane.

Compositions and compounds disclosed herein alternatively areadministered by aerosol. This is accomplished by preparing an aqueousaerosol, liposomal preparation or solid particles containing thecompound. In some embodiments, a non-aqueous (e.g., fluorocarbonpropellant) suspension is used. In some embodiments, sonic nebulizersare used because they minimize exposing the agent to shear, whichresults in degradation of the compounds contained in the subjectcompositions. Ordinarily, an aqueous aerosol is made by formulating anaqueous solution or suspension of a subject composition together withconventional pharmaceutically acceptable carriers and stabilizers. Thecarriers and stabilizers vary with the requirements of the particularsubject composition, but typically include non-ionic surfactants(Tweens, Pluronics, or polyethylene glycol), innocuous proteins likeserum albumin, sorbitan esters, oleic acid, lecithin, amino acids suchas glycine, buffers, salts, sugars or sugar alcohols. Aerosols generallyare prepared from isotonic solutions.

Pharmaceutical compositions suitable for parenteral administrationcomprise a subject composition in combination with one or morepharmaceutically-acceptable sterile isotonic aqueous or non-aqueoussolutions, dispersions, suspensions or emulsions, or sterile powderswhich are reconstituted into sterile injectable solutions or dispersionsjust prior to use, which, in some embodiments, contain antioxidants,buffers, bacteriostats, solutes which render the formulation isotonicwith the blood of the intended recipient or suspending or thickeningagents.

Examples of suitable aqueous and non-aqueous carriers which are employedin the pharmaceutical compositions include water, ethanol, polyols (suchas glycerol, propylene glycol, polyethylene glycol, and the like), andsuitable mixtures thereof, vegetable oils, such as olive oil, andinjectable organic esters, such as ethyl oleate and cyclodextrins.Proper fluidity is maintained, for example, by the use of coatingmaterials, such as lecithin, by the maintenance of the required particlesize in the case of dispersions, and by the use of surfactants

The dose of the composition comprising at least one compound describedherein differs, depending upon the patient's (e.g., human) condition,that is, stage of the disease, general health status, age, and otherfactors.

Pharmaceutical compositions are administered in a manner appropriate tothe disease to be treated (or prevented). An appropriate dose and asuitable duration and frequency of administration will be determined bysuch factors as the condition of the patient, the type and severity ofthe patient's disease, the particular form of the active ingredient, andthe method of administration. In general, an appropriate dose andtreatment regimen provides the composition(s) in an amount sufficient toprovide therapeutic and/or prophylactic benefit (e.g., an improvedclinical outcome, such as more frequent complete or partial remissions,or longer disease-free and/or overall survival, or a lessening ofsymptom severity). Optimal doses are generally determined usingexperimental models and/or clinical trials. In some embodiments, theoptimal dose depends upon the body mass, weight, or blood volume of thepatient.

Oral doses typically range from about 1.0 mg to about 1000 mg, one tofour times, or more, per day.

Dose administration can be repeated depending upon the pharmacokineticparameters of the dosage formulation and the route of administrationused.

It is especially advantageous to formulate compositions in dosage unitform for ease of administration and uniformity of dosage. Dosage unitform as used herein refers to physically discrete units suited asunitary dosages for the mammalian subjects to be treated; each unitcontaining a predetermined quantity of active compound calculated toproduce the desired therapeutic effect in association with the requiredpharmaceutical carrier. The specification for the dosage unit forms aredictated by and directly dependent on (a) the unique characteristics ofthe RORγ modulator and the particular therapeutic effect to be achievedand (b) the limitations inherent in the art of compounding such anactive compound for the treatment of sensitivity in individuals. Thespecific dose can be readily calculated by one of ordinary skill in theart, e.g., according to the approximate body weight or body surface areaof the patient or the volume of body space to be occupied. The dose willalso be calculated dependent upon the particular route of administrationselected. Further refinement of the calculations necessary to determinethe appropriate dosage for treatment is routinely made by those ofordinary skill in the art. Such calculations can be made without undueexperimentation by one skilled in the art in light of the RORγ modulatoractivities disclosed herein in assay preparations of target cells. Exactdosages are determined in conjunction with standard dose-responsestudies. It will be understood that the amount of the compositionactually administered will be determined by a practitioner, in the lightof the relevant circumstances including the condition or conditions tobe treated, the choice of composition to be administered, the age,weight, and response of the individual patient, the severity of thepatient's symptoms, and the chosen route of administration.

Toxicity and therapeutic efficacy of such RORγ modulators can bedetermined by standard pharmaceutical procedures in cell cultures orexperimental animals, for example, for determining the LD₅₀ (the doselethal to 50% of the population) and the ED₅₀ (the dose therapeuticallyeffective in 50% of the population). The dose ratio between toxic andtherapeutic effects is the therapeutic index and it can be expressed asthe ratio LD₅₀/ED₅₀. RORγ modulators that exhibit large therapeuticindices are preferred. While RORγ modulators that exhibit toxic sideeffects may be used, care should be taken to design a delivery systemthat targets such modulators to the site of affected tissue in order tominimize potential damage to uninfected cells and, thereby, reduce sideeffects.

The data obtained from the cell culture assays and animal studies can beused in formulating a range of dosage for use in humans. The dosage ofsuch RORγ modulators lies preferably within a range of circulatingconcentrations that include the ED₅₀ with little or no toxicity. Thedosage may vary within this range depending upon the dosage formemployed and the route of administration utilized. For any RORγmodulator used in a method described herein, the therapeuticallyeffective dose can be estimated initially from cell culture assays. Adose may be formulated in animal models to achieve a circulating plasmaconcentration range that includes the IC₅₀ (i.e., the concentration ofRORγ modulator that achieves a half-maximal inhibition of symptoms) asdetermined in cell culture. Such information can be used to moreaccurately determine useful doses in humans. Levels in plasma may bemeasured, for example, by high performance liquid chromatography.

EXAMPLES

The following examples are offered for purposes of illustration, and arenot intended to limit the scope of the claims provided herein. Allliterature citations in these examples and throughout this specificationare incorporated herein by references for all legal purposes to beserved thereby. The starting materials and reagents used for thesynthesis of the compounds described herein may be synthesized or can beobtained from commercial sources, such as, but not limited to,Sigma-Aldrich, Acros Organics, Fluka, and Fischer Scientific.

Standard abbreviations and acronyms as defined in J. Org. Chem. 200772(1): 23A-24A are used herein. Other abbreviations and acronyms usedherein are as follows:

AcOH acetic acid DCM dichloromethane DMP Dess-Martin periodinane dppf(diphenylphosphino)ferrocene EtOAc ethyl acetate HBTUN,N,N′,N′-tetramethyl-O-(1H-benzotriazol- 1-yl)uroniumhexafluorophosphate LC-MS liquid chromatography-mass spectrometry MeOHmethanol TEA triethylamine rt room temperature

General Synthetic Scheme:

General Procedure

Aldehyde (1) (1.0 equiv) and secondary amine (2) (1.2 equiv) werecombined in 1,2-DCE with catalytic amount of acid such as acetic acid orTFA. The mixture was stirred at rt for 1 h to 3 h. NaBH(OAc)₃ (3.0equiv) was added to the solution. The resulting mixture was stirred atroom temperature overnight. The reaction was quenched with MeOH andextracted with ethyl acetate (2×20 mL). The crude mixture was purifiedon a silica gel column to afford clean product (3).

Example A: Synthesis of Aldehyde Intermediate Synthesis of Intermediate1, Intermediate 2 and Intermediates 2A-2D

Step A. To a solution of2-(4-aminophenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (4) (15.0 g, 1.0equiv) in DMF (120 mL) was added a solution of NaNO₂ (4.4 g, 1.1 equiv)in 30 mL water. The mixture was cooled to 0° C. for 15 min. 6 N HCl (29mL, 3.0 equiv) was added dropwise to the reaction mixture over 15 min at0° C. The resulting mixture was stirred at 0° C. for 1 h. KI (10.1 g,1.05 equiv) was added with portions (over 15 mins). The reaction mixturewas stirred at 0° C. for 1 h, and then at room temperature overnight.The reaction was diluted with water (˜500 mL) and extracted withEtOAc/hexane (2:1, 3×150 mL). The combined organic phase was washed withNaHSO₃, water, and brine. The crude mixture was purified on a silica gelcolumn to afford 1,1,1,3,3,3-hexafluoro-2-(4-iodophenyl)propan-2-ol(Intermediate 1) (18.9 g, yield 88%) as a pale yellow oil.

Procedure 1, Step B. To a solution of compound Intermediate 1 (1.0 g,1.0 equiv) in anhydrous 1,4-dioxane (20 mL) was addedbis(pinacolato)diboron (0.89 g, 1.3 equiv), potassium acetate (0.265 g,3.0 equiv), and Pd(dppf)₂Cl₂ (100 mg, 0.05 equiv). The mixture wasdegassed and then bubbled with N₂ for 5 min, and then stirred at 90° C.overnight. Upon cooling to room temperature, the mixture was poured intoNH₄Cl solution and extracted with DCM. The organic phase was dried overMgSO₄, concentrated, and purified with silica gel column chromatographyto afford1,1,1,3,3,3-hexafluoro-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-ol(Intermediate 2) (450 mg, yield 45%) as a white solid.

1,1,1,3,3,3-Hexafluoro-2-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-ol(Intermediate 2A) was prepared as described in Step B substituting2-(4-bromo-3-methylphenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol forIntermediate 1.

2-(3-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol(Intermediate 2B) was prepared as described in Step B substituting2-(4-bromo-3-ethylphenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol forIntermediate 1.

1,1,1,3,3,3-hexafluoro-2-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-ol(Intermediate 2C) was prepared as described in Step B substituting2-(4-bromo-3-fluorophenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol forIntermediate 1.

2-(3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol(Intermediate 2D) was prepared as described in Step B substituting2-(4-bromo-3-chlorophenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol forIntermediate 1.

Example B: Synthesis of2-(4-bromo-3-fluorophenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol(Intermediate 3) and2-(4-bromo-3-methylphenyl)-1,1,1,3,3,3-hexafluoropropan-2-olIntermediate 4

Methyl 4-bromo-3-methylbenzoate (5) (1.0 g, 1.0 equiv) was dissolved in20 mL THF and TMSCF₃ (3.1 g, 5.0 equiv) was added. The mixture wascooled at −15° C. To the mixture was added 1M TBAF (13 mL, 3.0 equiv)dropwise over 20 min. After addition of TMSCF₃, 1N HCl (80 mL) was addedslowly. The mixture was stirred at rt for 15 min and then extracted with2×40 mL hexane. The organic phase was dried over MgSO₄ and concentratedin vacuum to afford (6) (0.98 g) that was used for the next reactionwithout purification. The intermediate (6) and TMSCF₃ (3.0 g) wasdissolved in anhydride THF (20 mL) and cooled with ice-water. TBAF (1M,5 mL) was added dropwise. The resulting mixture was stirred at 0° C. for2 h. The reaction was quenched with 1N HCl (80 mL). The mixture wasextracted with 2×40 mL hexane. The crude mixture was purified on asilica gel column to afford2-(4-bromo-3-methylphenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol(Intermediate 4) (420 mg, yield 29% in two-steps) as a white solid.

2-(4-bromo-3-fluorophenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol(Intermediate 3) was synthesized as described in this Example B, byreplacing methyl 4-bromo-3-methylbenzoate with 4-bromo-3-fluorobenzoate.

Example C: Synthesis of2-ethyl-4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1′-biphenyl]-4-carbaldehyde(Aldehyde Intermediate 5)

Step A. 4-bromo-3-ethylbenzoic acid (7) (5.0 g, 1.0 equiv),N,O-dimethylhydroxylamine hydrochloride (3.2 g, 1.5 equiv) and HBTU (9.6g, 1.15 equiv) were combined in 80 mL DMF at room temperature. To thereaction mixture was added Et₃N (11.2 g, 4.0 equiv) dropwise. Theresulting mixture was stirred at rt overnight. The reaction was dilutedwith 200 mL of ethyl acetate and 100 mL of hexane, then washed with2×150 mL water, 2×100 mL 1N HCl, 2×100 mL saturated NaHCO₃, and brine.The organic phase was dried over MgSO₄ and concentrated in vacuum toprovide 4-bromo-3-ethyl-N-methoxy-N-methylbenzamide (8) (5.8 g, yield98%) as a pale yellow oil which was used without further purification.

Step B. 4-Bromo-3-ethyl-N-methoxy-N-methylbenzamide (8) (3.0 g, 1.0equiv) and 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane)(3.2 g, 1.15 equiv) were dissolved in dry dioxane (25 mL). The mixturewas degassed by bubbling N₂ for 5 min. PdCl₂ (dppf) (0.81 g, 0.1 equiv)and potassium acetate (1.6 g, 1.5 equiv) were added to the reactionmixture. The resulting mixture was heated at 100° C. in a sealed-tubefor 15 h. The reaction mixture was diluted with 80 mL acetate and 80 mLhexane, washed with 3×80 mL water and 50 mL brine. The crude mixture waspurified on a silica gel column to afford3-ethyl-N-methoxy-N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(9) (3.3 g, yield 95%) as a pale yellow oil.

Step C.3-ethyl-N-methoxy-N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(9) (2.24 g, 1.0 equiv),1,1,1,3,3,3-hexafluoro-2-(4-iodophenyl)propan-2-ol (2.85 g, 1.1 equiv),Pd(PPh₃)₄ (0.81 g, 0.1 equiv) and K₂CO₃ (2.9 g, 3.0 equiv) were combinedin 35 mL dioxane and 10 mL water. The mixture was flushed with N₂ for 5min, and then heated at 95° C. for 14 h under N₂. The reaction wasextracted with EtOAc (2×200 mL). The combined organic phase was washedwith 1N HCl and brine. The crude mixture was purified on a silica gelcolumn to afford2-ethyl-4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-N-methoxy-N-methyl-[1,1′-biphenyl]-4-carboxamide(2.28 g, yield 75%) as a white solid.

2-ethyl-4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-N-methoxy-N-methyl-[1,1′-biphenyl]-4-carboxamide(2.0 g, 1.0 equiv) was dissolved in dry THF (20 mL) and the solution wascooled to −50° C. under N₂. LAH (4.6 mL, 1.0 equiv) was added dropwise.The mixture was stirred at −30° C. to −10° C. for an additional 40 min.The reaction was quenched with 1 mL water at −10° C. and then dilutedwith 50 mL 2N HCl. The mixture was extracted with 2×50 mL of ethylacetate. The crude mixture was purified on a silica gel column toprovide2-ethyl-4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1′-biphenyl]-4-carbaldehyde(Aldehyde Intermediate 5) (1.41 g, yield 82%) as a white solid.

Example D: Synthesis of2-ethyl-6-fluoro-4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1′-biphenyl]-4-carbaldehyde(Aldehyde Intermediate 6)

To a solution of 3-fluoro-2-hydroxybenzaldehyde (1.4 g, 10 mmol) in THF(20 mL) was added MeMgCl (8 mL, 24 mmol) at 0° C. The reaction mixturewas stirred at 0° C. to rt for 1 h, diluted with EtOAc, and quenchedwith saturated NH₄Cl. The organic layer was dried and evaporated toafford crude 2-fluoro-6-(1-hydroxyethyl)phenol (1.4 g).

To a solution of 2-fluoro-6-(1-hydroxyethyl)phenol (1.4 g) in MeOH (20mL) was added 10% Pd/C (100 mg) and hydrogenated under hydrogen (50 PSI)overnight. The mixture was filtered through Celite and the filtrationwas concentrated to give 2-ethyl-6-fluorophenol (1.0 g).

To a solution of 2-ethyl-6-fluorophenol (1 g, 7.1 mmol) in AcOH (10 mL)was added NBS (1.3 g) at 0° C. The reaction mixture was stirred at 0° C.to rt for 1 h, diluted with EtOAc, and washed with water. The organiclayer was concentrated and purified on a silica gel column to give4-bromo-2-ethyl-6-fluorophenol (0.9 g).

The mixture of 4-bromo-2-ethyl-6-fluorophenol (0.88 g, 4 mmol), Zn(CN)₂(0.93 g, 8 mmol) and Pd(PPh₃)₄ (100 mg, 0.09 mmol) in toluene (10 mL)was heated at 90° C. under N₂ overnight. The mixture was cooled to rtand washed with water and brine. The organic layer was concentrated andpurified on a silica gel column to give3-ethyl-5-fluoro-4-hydroxybenzonitrile (0.35 g).

To a solution of 3-ethyl-5-fluoro-4-hydroxybenzonitrile (0.34 g, 2.0mmol) in CH₂Cl₂ (10 mL) was added DIBAL (4.5 mL, 4.5 mmol) at −78° C.under N₂. The reaction mixture was stirred at −78° C. to 0° C. for 2 hand then quenched with 1N HCl. The organic layer was concentrated andpurified on a silica gel column to give3-ethyl-5-fluoro-4-hydroxybenzaldehyde (0.17 g).

To a solution of 3-ethyl-5-fluoro-4-hydroxybenzaldehyde (0.17 g, 1 mmol)in CH₂Cl₂ (10 mL) was added N(Et)₃ (0.2 g, 2 mmol) at 0° C. followed byaddition of (Tf)₂O (0.28 g, 1 mmol) under N₂. The reaction mixture wasstirred at 0° C. to 2 h and quenched with water. The organic layer wasconcentrated and purified on a silica gel column to give2-ethyl-6-fluoro-4-formylphenyl trifluoromethanesulfonate (0.15 g).

A mixture of 2-ethyl-6-fluoro-4-formylphenyl trifluoromethanesulfonate(0.15 g, 0.5 mmol),1,1,1,3,3,3-hexafluoro-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-ol(Intermediate 2) (0.15 g), Pd(PPh₃)₄ (55 mg), and Na₂CO₃ (2N solution,0.5 mL) in dioxane (10 mL) was heated at 90° C. under N₂ overnight. Themixture was cooled to rt and washed with water and brine. The organiclayer was concentrated and purified on a silica gel column to afford2-ethyl-6-fluoro-4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1′-biphenyl]-4-carbaldehyde(Aldehyde Intermediate 6) (85 mg).

Example E: Synthesis of2-ethyl-5-fluoro-4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1′-biphenyl]-4-carbaldehyde(Aldehyde Intermediate 7)

To a solution of 1-(4-fluoro-3-nitrophenyl)ethan-1-one (1.8 g, 10 mmol)in THF (20 mL) was added NaBH₄ (0.38 g, 10 mmol) at 0° C. The reactionmixture was stirred at 0° C. to rt for 1 h, diluted with EtOAc, andquenched with saturated NH₄Cl. The organic layer was dried andevaporated to afford 1-(4-fluoro-3-nitrophenyl)ethan-1-ol (1.5 g).

To a solution of 1-(4-fluoro-3-nitrophenyl)ethan-1-ol (1.5 g) in MeOH(20 mL) was added 10% Pd/C (100 mg) and hydrogenated under hydrogen (50PSI) overnight. The mixture was filtered through Celite and thefiltration was concentrated to give 5-ethyl-2-fluoroaniline (1.0 g).

To a solution of 5-ethyl-2-fluoroaniline (0.62 g, 4.4 mmol) in DMF (10mL) was added NBS (0.83 g) at 0° C. The reaction mixture was stirred at0° C. to rt for 1 h, diluted with EtOAc, and washed with water. Theorganic layer was concentrated and purified by flash cartridge (ISCO) togive 4-bromo-5-ethyl-2-fluoroaniline (0.92 g).

To a solution of 4-bromo-5-ethyl-2-fluoroaniline (0.88 g, 4 mmol) in H₂O(15 mL) was added H₂SO₄ (4 mL, 2N solution). The mixture was sonicatedfor 30 mins and cooled to 0° C. NaNO₂ (0.3 g, 4.4 mmol) in water (10 mL)was added dropwise. After stirring at 0° C. for 1 h, Na₂CO₃ was added toadjust pH to 7. The aqueous mixture was added to KCN (0.52 g. 8 mmol)and CuCN (0.36 g, 4 mmol) in water at 70° C. and the mixture was stirredat 70° C. for 2 h and extracted with EtOAc. The organic layer was washedwith water, brine and concentrated, the residue was purified by flashcartridge (ISCO) to give 4-bromo-5-ethyl-2-fluorobenzonitrile (0.35 g).

To a solution of 4-bromo-5-ethyl-2-fluorobenzonitrile compound (0.34 g,2 mmol) in CH₂Cl₂ (10 mL) was added DIBAL (2.2 mL, 2.2 mmol) at −78° C.under N₂. The reaction mixture was stirred at −78° C. to 0° C. for 2 hand quenched with 1N HCl. The organic layer was concentrated andpurified by flash cartridge (ISCO) to afford4-bromo-5-ethyl-2-fluorobenzaldehyde (0.15 g).

A mixture of 4-bromo-5-ethyl-2-fluorobenzaldehyde (0.11 g, 0.5 mmol),1,1,1,3,3,3-hexafluoro-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-ol(0.15 g), Pd(PPh₃)₄ (55 mg), and Na₂CO₃ (2N solution, 0.5 mL) in dioxane(10 mL) was heated at 90° C. under N₂ overnight. The mixture was cooledto rt and washed with water and brine. The organic layer wasconcentrated and purified by flash cartridge (ISCO) to give compound2-ethyl-5-fluoro-4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1′-biphenyl]-4-carbaldehyde(52 mg).

Example F: Synthesis of2-ethyl-3-fluoro-4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1′-biphenyl]-4-carbaldehyde(Aldehyde Intermediate 8)

To a solution of 4-bromo-2-fluoro-1-iodobenzene (3.0 g, 10 mmol) in THF(20 mL) was added LDA (12 mL, 12 mmol) at −78° C. under N₂. The reactionwas slowly warmed to −20° C. and then cooled to −78° C. EtI (4.7 g, 30mmol) was added. The mixture was stirred at −78° C. to rt overnight,diluted with EtOAc, and washed with water. The organic layer wasconcentrated and purified by flash cartridge (ISCO) to give1-bromo-2-ethyl-3-fluoro-4-iodobenzene (1.2 g).

The mixture of 1-bromo-2-ethyl-3-fluoro-4-iodobenzene (1.0 g, 3.0 mmol),Zn(CN)₂ (0.19 g, 1.6 mmol) and Pd(PPh₃)₄ (0.17 g, 0.15 mmol) in toluene(10 mL) was heated at 70° C. under N₂ overnight. The mixture was cooledto r.t. and washed with water and brine. The organic layer wasconcentrated and purified by flash cartridge (ISCO) to give4-bromo-3-ethyl-2-fluorobenzonitrile (0.25 g).

To a solution of 4-bromo-3-ethyl-2-fluorobenzonitrile (0.17 g, 1.0 mmol)in CH₂Cl₂ (10 mL) was added DIBAL (1.1 mL, 1.1 mmol) at −78° C. underN₂. The reaction mixture was stirred at −78° C. to 0° C. for 2 h andquenched with 1N HCl. The organic layer was concentrated and purified byflash cartridge (ISCO) to 4-bromo-3-ethyl-2-fluorobenzaldehyde (0.12 g).

A mixture of 4-bromo-3-ethyl-2-fluorobenzaldehyde (0.11 g, 0.5 mmol),1,1,1,3,3,3-hexafluoro-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-ol(Intermediate 2) (0.15 g), Pd(PPh₃)₄ (55 mg), and Na₂CO₃ (2N solution,0.5 mL) in dioxane (10 mL) was heated at 90° C. under N₂ overnight. Themixture was cooled to rt and washed with water followed by brine. Theorganic layer was concentrated and purified by flash cartridge (ISCO) togive2-ethyl-3-fluoro-4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1′-biphenyl]-4-carbaldehyde(48 mg).

Example G: Synthesis of4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2-isopropyl-[1,1′-biphenyl]-4-carbaldehyde(Aldehyde Intermediate 9) and2-(sec-butyl)-4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1′-biphenyl]-4-carbaldehyde(Aldehyde Intermediate 10)

Step A. To a solution of 2-isopropylphenol (6.5 g, 48 mmol, 1.0 equiv)in 50% aqueous NaOH (30 mL) was added Cu powder (240 mg) and carbontetrachloride (6.7 mL, 62 mmol, 1.3 equiv). The mixture was heated atreflux for 16 h. Upon cooling, the mixture was acidified to pH 2 byaddition of concentrated HCl and was extracted with EtOAc. The organicphase was then extracted with saturated NaHCO₃ solution and the aqueouslayer was acidified to pH 2 by careful titration with concentrated HCl.The solution was extracted with EtOAc. The organic layer was washed withwater, separated and concentrated to dryness to afford4-hydroxy-3-isopropylbenzoic acid (4 g) as a bright red solid which wasused without further purification.

Step B. To a mixture of 4-hydroxy-3-isopropylbenzoic acid (2.0 g, 11mmol, 1 equiv), triethylamine (3.30 g, 33 mmol, 3 equiv), andN,O-dimethylhydroxylamine hydrochloride (1.08 g, 110 mmol, 10 equiv) inDCM (100 mL) was added HBTU (6.25 g, 1.65 mmol, 1.5 equiv). The mixturewas stirred at room temperature overnight. The mixture was washed withsaturated NaHCO₃ solution, 2N HCl, and water. The organic phase wasdried over MgSO₄ and concentrated in vacuo to afford4-hydroxy-3-isopropyl-N-methoxy-N-methylbenzamide (4.5 g) as a pale redsolid which was used without further purification.

Step C. To a mixture of4-hydroxy-3-isopropyl-N-methoxy-N-methylbenzamide (500 mg, 2.2 mmol, 1equiv) and pyridine (525 μL, 6.6 mmol, 3 equiv) in DCM (30 ml) was addedtrifluoromethanesulfonic anhydride (0.93 g, 3.3 mmol, 1.5 equiv)dropwise at 0° C. The mixture was stirred at 0° C. for 1 h, and washedwith saturated NaHCO₃ solution and water. The organic phase was driedover MgSO₄, concentrated, and purified on a silica gel column to afford2-isopropyl-4-(methoxy(methyl)carbamoyl)phenyl trifluoromethanesulfonate(680 mg) as a white solid.

Step D. To a solution of 2-isopropyl-4-(methoxy(methyl)carbamoyl)phenyltrifluoromethanesulfonate (680 mg, 1.9 mmol, 1 equiv) in anhydrous1,4-dioxane (20 mL) was added bis(pinacolato)diboron (0.63 g, 2.5 mmol,1.3 equiv), potassium acetate (0.56 g, 5.7 mmol, 3 equiv), andPd(dppf)₂Cl₂ (70 mg, 0.095 mmol, 0.05 equiv). The mixture was degassedand then bubbled with N₂ for 5 min, and then stirred at 90° C. for 3 h.Upon cooling to room temperature, the mixture was poured into NH₄Clsolution and extracted with DCM. The organic phase was dried over MgSO₄,concentrated, and purified on a silica gel column to afford3-isopropyl-N-methoxy-N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(500 mg) as a white solid.

Step E. To a solution of3-isopropyl-N-methoxy-N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(100 mg, 0.3 mmol, 1 equiv) in anhydrous 1,4-dioxane (2 mL) was added1,1,1,3,3,3-hexafluoro-2-(4-iodophenyl)propan-2-ol (Intermediate 1) (145mg, 0.39 mmol, 1.3 equiv), 2M potassium carbonate solution (0.45 ml, 0.9mmol, 3 equiv), and Pd(PPh₃)₄ (17 mg, 0.015 mmol, 0.05 equiv). Themixture was degassed and then bubbled with N₂ for 5 min, and thenstirred at 90° C. for 3 h. Upon cooling to room temperature, the mixturewas poured into NH₄Cl solution and extracted with DCM. The organic phasewas dried over MgSO₄, concentrated, and purified on a silica gel columnto afford3-isopropyl-N-methoxy-N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(100 mg) as a white solid.

Step F. To a solution of3-isopropyl-N-methoxy-N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(100 mg, 0.22 mmol, 1.0 equiv) in anhydrous THF (2 mL) was added 1.0 MLAH solution in THF (220 μL, 1.0 equiv) at −78° C. The reaction wasstirred at −78° C. for 1 h and quenched by adding EtOAc before beingwarmed to room temperature. The mixture was poured into NH₄Cl solutionand extracted with DCM. The organic phase was dried over MgSO₄,concentrated, and purified on a silica gel column to afford4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2-isopropyl-[1,1′-biphenyl]-4-carbaldehyde(Aldehyde Intermediate 9) (90 mg) as a white solid.

Aldehyde Intermediate 10 was prepared using the same method butsubstituting 2-(sec-butyl)phenol for 2-isopropanol phenol.

Example H: Synthesis of3,6-difluoro-4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2-isopropyl-[1,1′-biphenyl]-4-carbaldehyde(Aldehyde Intermediate 11)

Step A. 2,5-difluoro-4-methoxybenzoic acid (500 mg) was treated withBBr₃ at room temperature for 24 h. The reaction was worked up with 2NHCl, and purified on a silica gel column to give2,5-difluoro-4-hydroxybenzoic acid.

Step B. To a mixture of 2,5-difluoro-4-hydroxybenzoic acid (380 mg, 2.18mmol, 1 equiv), triethylamine (660 mg, 6.6 mmol, 3 equiv) andN,O-dimethylhydroxylamine hydrochloride (2.14 g, 21.8 mmol, 10 equiv) inDCM (20 mL) was added HBTU (1.25 g, 3.27 mmol, 1.5 equiv). The mixturewas stirred at room temperature overnight, then washed with saturatedNaHCO₃ solution, 2N HCl, and water. The organic phase was dried overMgSO₄, concentrated, and purified on a silica gel column to afford2,5-difluoro-4-hydroxy-N-methoxy-N-methylbenzamide (190 mg) as acolorless oil.

Step C. To a solution of2,5-difluoro-4-hydroxy-N-methoxy-N-methylbenzamide (190 mg, 0.87 mmol, 1equiv) in acetic acid (4 mL) was added NBS (190 mg, 1.05 mmol, 1.2equiv) at 0° C. The reaction was warmed to rt and stirred for 2 h. Thesolvent was removed in high vacuo, the residue was dissolved in EtOAc,washed with water, concentrated, and purified on a silica gel column toafford 3-bromo-2,5-difluoro-4-hydroxy-N-methoxy-N-methylbenzamide (240mg) as a white solid.

Step D. To a solution of3-bromo-2,5-difluoro-4-hydroxy-N-methoxy-N-methylbenzamide (240 mg, 0.81mmol, 1 equiv) in anhydrous 1,4-dioxane (9 mL) was addedisopropenylboronic acid pinacol ester (204 mg, 1.22 mmol, 1.5 equiv), 2Mpotassium carbonate solution (1.2 mL, 2.4 mmol, 3 equiv), and Pd(PPh₃)₄(45 mg, 0.04 mmol, 0.05 equiv). The mixture was degassed and thenbubbled with N₂ for 5 min, and then stirred at 90° C. overnight. Uponcooling to room temperature, the mixture was poured into NH₄Cl solutionand extracted with DCM. The organic phase was dried over MgSO₄,concentrated, and purified on a silica gel column to afford2,5-difluoro-4-hydroxy-N-methoxy-N-methyl-3-(prop-1-en-2-yl)benzamide(180 mg) as a white solid.

Step E. To a mixture of2,5-difluoro-4-hydroxy-N-methoxy-N-methyl-3-(prop-1-en-2-yl)benzamide(180 mg, 0.7 mmol, 1 equiv) and pyridine (0.5 mL) in DCM (50 mL) wasadded trifluoromethanesulfonic anhydride (0.33 g, 1.05 mmol, 1.5 equiv)dropwise at 0° C. The mixture was stirred at 0° C. for 1 h and washedwith saturated NaHCO₃ solution and water. The organic phase was driedover MgSO₄, concentrated, and purified on a silica gel column to afford3,6-difluoro-4-(methoxy(methyl)carbamoyl)-2-(prop-1-en-2-yl)phenyltrifluoromethanesulfonate (240 mg) as a pale yellow oil.

Step F. To a solution of3,6-difluoro-4-(methoxy(methyl)carbamoyl)-2-(prop-1-en-2-yl)phenyltrifluoromethanesulfonate (240 mg, 0.61 mmol, 1 equiv) in anhydrous1,4-dioxane (10 mL) was added1,1,1,3,3,3-hexafluoro-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-ol(340 mg, 0.93 mmol, 1.5 equiv), 2M potassium carbonate solution (1.0 mL,1.8 mmol, 3 equiv), and Pd(PPh₃)₄ (35 mg, 0.03 mmol, 0.05 equiv). Themixture was degassed and then bubbled with N₂ for 5 min, and thenstirred at 90° C. overnight. Upon cooling to room temperature, themixture was poured into NH₄Cl solution and extracted with DCM. Theorganic phase was dried over MgSO₄, concentrated, and purified on asilica gel column to afford3,6-difluoro-4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-N-methoxy-N-methyl-2-(prop-1-en-2-yl)-[1,1′-biphenyl]-4-carboxamide(140 mg) as a white solid.

Step G. To a solution of3,6-difluoro-4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-N-methoxy-N-methyl-2-(prop-1-en-2-yl)-[1,1′-biphenyl]-4-carboxamide(140 mg, 0.29 mmol, 1 equiv) in MeOH (10 mL) was added Pd/C (10% wt., 14mg). The reaction was shaken under H₂ (50 psi) environment for 4 h. Themixture was filtered to remove catalyst and concentrated to afford3,6-difluoro-4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2-isopropyl-N-methoxy-N-methyl-[1,1′-biphenyl]-4-carboxamide(120 mg) as a white solid.

Step H. To a solution of3,6-difluoro-4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2-isopropyl-N-methoxy-N-methyl-[1,1′-biphenyl]-4-carboxamide(120 mg, 0.25 mmol, 1 equiv) in anhydrous THF (2 mL) was added 1.0 M LAHsolution in THF (250 μL, 1.0 equiv) at −78° C. The reaction was stirredat −78° C. for 1 h and quenched by adding EtOAc before being warmed toroom temperature. The mixture was poured into NH₄Cl solution andextracted with DCM. The organic phase was dried over MgSO₄,concentrated, and purified on a silica gel column to afford3,6-difluoro-4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2-isopropyl-[1,1′-biphenyl]-4-carbaldehyde(Aldehyde Intermediate 11) (100 mg) as a white solid.

Synthesis of3,5-difluoro-4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2-isopropyl-[1,1′-biphenyl]-4-carbaldehyde(Aldehyde Intermediate 12)

Aldehyde Intermediate 12 was prepared using the above methods bysubstituting 2,6-difluoro-4-hydroxybenzoic acid for2,5-difluoro-4-hydroxybenzoic acid.

Example I: Synthesis of2-(tert-butyl)-4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1′-biphenyl]-4-carbaldehyde(Aldehyde Intermediate 13)

Step A. To a mixture of 3-(tert-butyl)-4-hydroxybenzoic acid (300 mg, 1equiv), TEA (470 mg, 3 equiv) and N,O-dimethylhydroxylaminehydrochloride (1.51 g, 10 equiv) in DCM (20 mL) was added HBTU (0.88 g,1.5 equiv). The mixture was stirred at room temperature overnight. Themixture was washed with saturated NaHCO₃ solution, 2N HCl, and water.The organic phase was dried over MgSO₄, concentrated, and purified on asilica gel column to afford3-(tert-butyl)-4-hydroxy-N-methoxy-N-methylbenzamide (202 mg, yield 55%)as a colorless oil.

Step B. To a mixture of3-(tert-butyl)-4-hydroxy-N-methoxy-N-methylbenzamide (202 mg, 1 equiv)and pyridine (0.6 mL) in DCM (50 mL) was added trifluoromethanesulfonicanhydride (0.36 g, 1.5 equiv) dropwise at 0° C. The mixture was stirredat 0° C. for 1 h, and washed with saturated NaHCO₃ solution and water.The organic phase was dried over MgSO₄, concentrated, and purified on asilica gel column to afford2-(tert-butyl)-4-(methoxy(methyl)carbamoyl)phenyltrifluoromethanesulfonate (220 mg) as a pale yellow oil.

Step C. To a solution of2-(tert-butyl)-4-(methoxy(methyl)carbamoyl)phenyltrifluoromethanesulfonate (240 mg, 1 equiv) in anhydrous 1,4-dioxane (10mL) was added1,1,1,3,3,3-hexafluoro-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-ol(330 mg, 1.5 equiv), 2M potassium carbonate solution (1.1 mL, 3 equiv),and Pd(PPh₃)₄ (38 mg, 0.05 equiv). The mixture was degassed and thenbubbled with N₂ for 5 min, and then stirred at 90° C. overnight. Uponcooling to room temperature, the mixture was poured into NH₄Cl solutionand extracted with DCM. The organic phase was dried over MgSO₄,concentrated, and purified on a silica gel column to afford2-(tert-butyl)-4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-N-methoxy-N-methyl-[1,1′-biphenyl]-4-carboxamide(183 mg, yield 75%) as a white solid.

Step D. To a solution of2-(tert-butyl)-4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-N-methoxy-N-methyl-[1,1′-biphenyl]-4-carboxamide(183 mg, 1.0 equiv) in anhydrous THF (2 mL) was added 1.0 M LAH solutionin THF (450 μL, 1.0 equiv) at −78° C. The reaction was stirred at −78°C. for 1 h and quenched by adding EtOAc before being warmed to roomtemperature. The mixture was poured into NH₄Cl solution and extractedwith DCM. The organic phase was dried over MgSO₄, concentrated, andpurified on a silica gel column to afford2-(tert-butyl)-4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1′-biphenyl]-4-carbaldehyde(120 mg) as a white solid.

Example J: Synthesis of4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2-methyl-[1,1′-biphenyl]-4-carbaldehyde(Aldehyde Intermediate 14),2-chloro-4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1′-biphenyl]-4-carbaldehyde(Aldehyde Intermediate 15) and4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2-(trifluoromethyl)-[1,1′-biphenyl]-4-carbaldehyde(Aldehyde Intermediate 16)

(4-Formyl-2-methylphenyl)boronic acid (6.65 g, 1.0 equiv),1,1,1,3,3,3-hexafluoro-2-(4-iodophenyl)propan-2-ol (3.2 g, 1.2 equiv),Pd(PPh₃)₄ (2.05 g, 0.1 equiv) and K₂CO₃ (7.4 g, 3.0 equiv) were combinedin dioxane (150 mL) and water (40 mL). The mixture was flushed with N₂for 5 min, and then heated at 80° C. for 8 h under N₂. The reaction wasextracted with EtOAc (2×200 mL). The combined organic phase was washedwith 1N HCl and brine. The crude mixture was purified on a silica gelcolumn to afford4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2-methyl-[1,1′-biphenyl]-4-carbaldehyde(4.6 g, yield 73%) as a white solid.

Aldehyde Intermediate 15 was prepared using the same method, butsubstituting (2-chloro-4-formylphenyl)boronic acid for(4-formyl-2-methylphenyl)boronic acid.

Aldehyde Intermediate 16 was prepared using the same method, butsubstituting (4-formyl-2-(trifluoromethyl)phenyl)boronic acid for(4-formyl-2-methylphenyl)boronic acid.

Example K: Synthesis of2-bromo-4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1′-biphenyl]-4-carbaldehyde(Aldehyde Intermediate 17)

Step A: Methyl3-amino-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (1.0 g,1.0 equiv), 1,1,1,3,3,3-hexafluoro-2-(4-iodophenyl)propan-2-ol (1.6 g,1.2 equiv), Pd(PPh₃)₄ (0.42 g, 0.1 equiv) and K₂CO₃ (1.5 g, 3.0 equiv)were combined in dioxane (30 mL) and water (10 mL). The mixture wasflushed with N₂ for 5 mins, and then heated at 80° C. for 8 h under N₂.The reaction was extracted with EtOAc (2×60 mL). The combined organicphase was washed with 1N HCl and brine. The crude mixture was purifiedon a silica gel column to afford methyl2-amino-4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1′-biphenyl]-4-carboxylate(1.16 g, yield 82%).

Step B: To a solution of methyl2-amino-4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1′-biphenyl]-4-carboxylateaniline (1.16 g, 1.0 equiv) in DMF (15 mL) was added a solution of NaNO₂(0.23 g, 1.1 equiv) in water (10 mL). The mixture was cooled to 0° C.for 15 mins. 6 N H₂SO₄ (9 mL, 3.0 equiv) was added dropwise to thereaction mixture for over 15 min at 0° C. The resulting mixture wasstirred at 0° C. for 1 h. CuBr (0.64 g, 1.5 equiv) was added. Thereaction mixture was stirred at 0° C. for 1 h and then rt overnight. Thereaction was diluted with water (˜500 mL) and extracted withEtOAc/Hexane (2:1, 3×150 mL). The combined organic phase was washed withNaHSO₃, water, and brine. The crude mixture was purified on a silica gelcolumn to afford methyl2-bromo-4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1′-biphenyl]-4-carboxylate(650 mg, yield 48%).

Step C: Methyl2-bromo-4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1′-biphenyl]-4-carboxylatewas converted to corresponding acid by treating with 2N LiOH in MeOH.The acid was coupled with N,O-dimethylhydroxylamine hydrochloride toafford2-bromo-4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-N-methoxy-N-methyl-[1,1′-biphenyl]-4-carboxamide.2-Bromo-4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-N-methoxy-N-methyl-[1,1′-biphenyl]-4-carboxamidewas converted to2-bromo-4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1′-biphenyl]-4-carbaldehydewith LAH reduction at −70° C.

Example L: Synthesis of4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2-(prop-1-en-2-yl)-[1,1′-biphenyl]-4-carbaldehyde(Aldehyde Intermediate 18)

Suzuki coupling between2-bromo-4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-N-methoxy-N-methyl-[1,1′-biphenyl]-4-carboxamideintermediate from Step C of Example K and4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane underreactions conditions described in Step A of Example K (except withheating to 90° C. overnight) afforded4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-N-methoxy-N-methyl-2-(prop-1-en-2-yl)-[1,1′-biphenyl]-4-carboxamidewhich was converted to the corresponding aldehyde,4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2-(prop-1-en-2-yl)-[1,1′-biphenyl]-4-carbaldehyde,with LAH reduction at −70° C.

Example M: Synthesis of2-cyclopropyl-4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1′-biphenyl]-4-carbaldehyde(Aldehyde Intermediate 19)

Suzuki coupling between2-bromo-4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-N-methoxy-N-methyl-[1,1′-biphenyl]-4-carboxamideintermediate from Step C of Example K and cyclopropylboronic acid underreactions conditions described in Step A of Example K (except withheating to 90° C. overnight) afforded2-cyclopropyl-4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-N-methoxy-N-methyl-[1,1′-biphenyl]-4-carboxamidewhich was converted to the corresponding aldehyde,2-cyclopropyl-4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1′-biphenyl]-4-carbaldehyde,with LAH reduction at −70° C.

Example N: Synthesis of4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2-isopropyl-2′-methyl-[1,1′-biphenyl]-4-carbaldehyde(Aldehyde Intermediate 20)

Standard Suzuki coupling between3-isopropyl-N-methoxy-N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide,the intermediate from Example F Step E, and Intermediate 4 afforded4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2-isopropyl-N-methoxy-N,2′-dimethyl-[1,1′-biphenyl]-4-carboxamidewhich was concerted to corresponding aldehyde with LAH reduction inanhydrous THF at −78° C.

Example O: Synthesis of2-ethyl-2′-fluoro-4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1′-biphenyl]-4-carbaldehyde(Aldehyde Intermediate 21) and2-ethyl-4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2′-methyl-[1,1′-biphenyl]-4-carbaldehyde(Aldehyde Intermediate 22)

Standard Suzuki coupling between3-ethyl-N-methoxy-N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamidefrom Step B of Example C and2-(4-bromo-3-fluorophenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol(Intermediate 3) afforded2-ethyl-2′-fluoro-4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-N-methoxy-N-methyl-[1,1′-biphenyl]-4-carboxamidewhich was converted to the corresponding aldehyde2-ethyl-2′-fluoro-4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1′-biphenyl]-4-carbaldehyde(Aldehyde Intermediate 21) with LAH reduction in anhydrous THF at −70°C.

Standard Suzuki coupling between3-ethyl-N-methoxy-N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamidefrom Step B of Example C and2-(4-bromo-3-methylphenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol(Intermediate 4) afforded2-ethyl-4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2′-methyl-[1,1′-biphenyl]-4-carbaldehydewhich was converted to the corresponding aldehyde2-ethyl-4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2′-methyl-[1,1′-biphenyl]-4-carbaldehyde(Aldehyde Intermediate 22) with LAH reduction in anhydrous THF at −70°C.

Example P: Synthesis of2-(pyridin-4-ylmethyl)-2,6-diazaspiro[3.3]heptane TFA (AmineIntermediate 1)

Commercially available oxalate (100 mg, 1.2 equiv) and tert-butyl2,6-diazaspiro[3.3]heptane-2-carboxylate was suspended into 1,2-DCE (15mL), to which Et₃N (42 mg, 2.0 equiv) was added and stirred at rt for 30min. Isonicotinaldehyde (40 mg, 1.0 equiv) was added followed by aceticacid (30 μL). The mixture was stirred at rt for 3 h and NaBH(OAc)₃ (240mg, 3.0 equiv) was added to the solution. The resulting mixture wasstirred at rt overnight. The reaction was quenched with MeOH and dilutedwith saturated NaHCO₃, then extracted with 2×20 mL DCM. The crudemixture was purified on a silica gel column to afford tert-butyl6-(pyridin-4-ylmethyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (70 mg,yield 65%). The carboxylate was treated with TFA (3 mL) in DCM (80% v/v)to afford 2-(pyridin-4-ylmethyl)-2,6-diazaspiro[3.3]heptane which wasused without purification.

Example Q: Synthesis of 2-(methylsulfonyl)-2,6-diazaspiro[3.3]heptaneTFA (Amine Intermediate 2), 2-(ethylsulfonyl)-2,6-diazaspiro[3.3]heptaneTFA (Amine Intermediate 3),2-(cyclopropylsulfonyl)-2,6-diazaspiro[3.3]heptane TFA (AmineIntermediate 4), 2-(propylsulfonyl)-2,6-diazaspiro[3.3]heptane TFA(Amine Intermediate 5) and2-(isobutylsulfonyl)-2,6-diazaspiro[3.3]heptane TFA (Amine Intermediate6)

tert-Butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate as oxalate salt (5.0g, 1.0 equiv) was suspended in CH₂Cl₂ (150 mL). To the mixture was addedsaturated NaHCO₃ (50 mL) at 0° C. The mixture was stirred at 0° C. for10 min and a solution of MsCl (4.7 g, 2.0 equiv) in CH₂Cl₂ (10 mL) wasadded dropwise. The resulting mixture was stirred at 0° C. for 1 h andthen at rt overnight. The organic phase was separated and washed withbrine, then concentrated in vacuum to afford tert-butyl6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate as a whitesolid (5.0 g, yield 88%) which was used without further purification.

tert-Butyl 6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptane-2-carboxylatewas treated with TFA in DCM (80% v/v) to afford2-(methylsulfonyl)-2,6-diazaspiro[3.3]heptane (Amine Intermediate 2),which was used without purification.

2-(ethylsulfonyl)-2,6-diazaspiro[3.3]heptane (Amine Intermediate 3) wassynthesized using the same methods using ethanesulfonyl chloride inplace of MsCl.

2-(cyclopropylsulfonyl)-2,6-diazaspiro[3.3]heptane (Amine Intermediate4) was synthesized using the same methods using cyclopropanesulfonylchloride in place of MsCl.

2-(propylsulfonyl)-2,6-diazaspiro[3.3]heptane (Amine Intermediate 5) wassynthesized using the same methods using propane-1-sulfonyl chloride inplace of MsCl.

2-(isobutylsulfonyl)-2,6-diazaspiro[3.3]heptane (Amine Intermediate 6)was synthesized using the same methods using 2-methylpropane-1-sulfonylchloride in place of MsCl.

Example R: Synthesis of 1-(2,6-diazaspiro[3.3]heptan-2-yl)ethan-1-oneTFA (Amine Intermediate 7) and methyl2,6-diazaspiro[3.3]heptane-2-carboxylate TFA (Amine Intermediate 8)

tert-Butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate as oxalate salt (100mg, 1.0 equiv) was suspended in CH₂Cl₂ (15 mL). To the mixture was addedsaturated NaHCO₃ (5 mL) at 0° C. The mixture was stirred at 0° C. for 10min, a solution of acetyl chloride (84 mg, 5.0 equiv) in CH₂Cl₂ (2 mL)was added dropwise. The resulting mixture was stirred at 0° C. for 1 h.The organic phase was separated and washed with brine, then concentratedin vacuum to afford tert-butyl6-acetyl-2,6-diazaspiro[3.3]heptane-2-carboxylate as a white solid (39mg, yield 75%) which was used without further purification.

tert-Butyl 6-acetyl-2,6-diazaspiro[3.3]heptane-2-carboxylate was treatedwith TFA in DCM (80% v/v) to afford1-(2,6-diazaspiro[3.3]heptan-2-yl)ethan-1-one (Amine Intermediate 7)which was used without purification.

Methyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (Amine Intermediate 8)was synthesized using the same method using methyl chloroformate inplace of acetyl chloride.

Example S: Synthesis of 2-thia-6-azaspiro[3.3]heptane 2-oxide (AmineIntermediate 9) and 6-thia-2-azaspiro[3.4]octane 6-oxide (AmineIntermediate 10)

To a solution of 2-thia-6-azaspiro[3.3]heptane (100 mg, 1.0 equiv) inDCM (8 mL) was added Et₃N (3.0 equiv) and (Boc)₂O (1.5 equiv). Theresulting mixture was stirred at rt overnight. The mixture was dried invacuo and purified on a silica gel column to afford tert-butyl2-thia-6-azaspiro[3.3]heptane-6-carboxylate (170 mg, yield 91%).

tert-Butyl 2-thia-6-azaspiro[3.3]heptane-6-carboxylate (60 mg, 1.0equiv) was dissolved in DCM (5 mL) and cooled to −30° C. mCPBA (64 mg,72%, 0.95 equiv) was added. The mixture was stirred at −30° C. for 10min, then at 0° C. for 1 h. The reaction mixture was diluted with DCM(20 mL) and washed with 3×10 mL saturated NaHCO₃. The crude mixture waspurified on a silica gel column to afford tert-butyl2-thia-6-azaspiro[3.3]heptane-6-carboxylate 2-oxide (48 mg, yield 74%).tert-Butyl 2-thia-6-azaspiro[3.3]heptane-6-carboxylate 2-oxide wastreated with TFA in DCM (80% v/v) to afford2-thia-6-azaspiro[3.3]heptane 2-oxide (Amine Intermediate 9) which wasused without purification.

Amine Intermediate 10 was synthesized using the same methods, using6-thia-2-azaspiro[3.4]octane in place of 2-thia-6-azaspiro[3.3]heptane.

Example T: Synthesis of 2-thia-6-azaspiro[3.3]heptane 2,2-dioxide TFA(Amine Intermediate 11) and 6-thia-2-azaspiro[3.4]octane 6,6-dioxide TFA(Amine Intermediate 12)

tert-Butyl 2-thia-6-azaspiro[3.3]heptane-6-carboxylate (60 mg, 1.0equiv) was dissolved in DCM (5 mL) and to cooled to 0° C. mCPBA (166 mg,72%, 2.5 equiv) was added. The mixture was stirred at 0° C. for 10 min,and then at rt for 1 h. The reaction mixture was diluted with DCM (20mL) and washed with 3×10 mL saturated NaHCO₃. The crude mixture waspurified on a silica gel column to afford tert-butyl2-thia-6-azaspiro[3.3]heptane-6-carboxylate 2,2-dioxide (56 mg, yield80%). tert-Butyl 2-thia-6-azaspiro[3.3]heptane-6-carboxylate 2,2-dioxidewas treated with TFA in DCM (80% v/v) to afford2-thia-6-azaspiro[3.3]heptane 2,2-dioxide TFA salt (Amine Intermediate11) which was used without purification.

Amine Intermediate 12 was synthesized using the same methods usingtert-butyl 6-thia-2-azaspiro[3.4]octane-2-carboxylate in place oftert-butyl 2-thia-6-azaspiro[3.3]heptane-6-carboxylate.

Example U: Synthesis of N-(azetidin-3-ylmethyl)methanesulfonamide TFA(Amine Intermediate 13)

Step A. tert-Butyl 3-(aminomethyl)azetidine-1-carboxylate (300 mg, 1.0equiv) and pyridine (1 mL) were combined in DCM (20 mL) at 0° C. MsCl(1.1 equiv) was added dropwise. The mixture was stirred at 0° C. for 3h. The reaction mixture was diluted with DCM (30 mL), washed with 3×30mL 1N HCl, water, and brine to afford tert-butyl3-(methylsulfonamidomethyl)azetidine-1-carboxylate (390 mg, yield 91%)which was used without further purification.

Step B. tert-Butyl 3-(methylsulfonamidomethyl)azetidine-1-carboxylatewas treated with TFA in DCM (80% v/v) to affordN-(azetidin-3-ylmethyl)methanesulfonamide TFA (Amine Intermediate 13)which was used without purification.

Example V: Synthesis ofN-(azetidin-3-ylmethyl)-N-methylmethanesulfonamide TFA (AmineIntermediate 14)

To a solution of tert-butyl3-(methylsulfonamidomethyl)azetidine-1-carboxylate from Step A ofExample U (100 mg, 1.0 equiv) in dry DMF (5 mL) was added NaH (60%, 23mg, 1.5 equiv). The mixture was stirred at rt for 30 min, and thencooled to 0° C. CH₃I (81 mg, 1.5 equiv) was added. The resulting mixturewas stirred at rt for 1 h. The reaction mixture was diluted with ethylacetate (20 mL) and hexane (20 mL). The mixture was washed with 3×30 mLwater and brine. The crude mixture was purified on a silica gel columnto afford tert-butyl3-((N-methylmethylsulfonamido)methyl)azetidine-1-carboxylate (72 mg,yield 68%).

tert-Butyl 3-((N-methylmethylsulfonamido)methyl)azetidine-1-carboxylatewas treated with TFA in DCM (80% v/v) to afford Amine Intermediate 14which was used without purification.

Example W: Synthesis of 2-(methylsulfonyl)-2,6-diazaspiro[3.4]octaneTFA(Amine Intermediate 15)

Commercially available tert-butyl2,6-diazaspiro[3.4]octane-6-carboxylate was treated with MsCl in thepresence of TEA to afford tert-butyl2-(methylsulfonyl)-2,6-diazaspiro[3.4]octane-6-carboxylate which wasnext treated with TFA in DCM (80% v/v) to afford Amine Intermediate 15which was used without purification.

Example X: Synthesis of 7-(methylsulfonyl)-2,7-diazaspiro[3.5]nonane TFA(Amine Intermediate 16)

Commercially available tert-butyl2,7-diazaspiro[3.5]nonane-2-carboxylate was treated with MsCl in thepresence of TEA to afford tert-butyl7-(methylsulfonyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate which wasthen treated with TFA in DCM (80% v/v) to afford Amine Intermediate 16as a TFA salt which was used without purification.

Example Y: Synthesis of 6-(methylsulfonyl)-2,6-diazaspiro[3.5]nonane TFA(Amine Intermediate 17)

Commercially available tert-butyl2,6-diazaspiro[3.5]nonane-2-carboxylate was treated with MsCl in thepresence of TEA to afford tert-butyl6-(methylsulfonyl)-2,6-diazaspiro[3.5]nonane-2-carboxylate which wasnext treated with TFA in DCM (80% v/v) to afford Amine Intermediate 17as a TFA salt which was used without purification.

Example Z: Synthesis of 2-(methylsulfonyl)-2,7-diazaspiro[4.4]nonane TFA(Amine Intermediate 19)

Commercially available tert-butyl2,7-diazaspiro[4.4]nonane-2-carboxylate was treated with MsCl in thepresence of TEA to afford tert-butyl7-(methylsulfonyl)-2,7-diazaspiro[4.4]nonane-2-carboxylate which wasnext treated with TFA in DCM (80% v/v) to afford Amine Intermediate 19as a TFA salt which was used without purification.

Example AA: Synthesis of 6-(methylsulfonyl)-2-azaspiro[3.3]heptane TFA(Amine Intermediate 20)

Commercially available tert-butyl6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (250 mg, 1.0 equiv), TEA(360 mg, 3.0 equiv) and DMAP (10 mg) were combined in DCM (25 mL) at 0°C. MsCl (162 mg, 1.2 equiv) was added dropwise. The mixture was stirredat 0° C. for 3 h. The reaction mixture was diluted with DCM (30 mL) andthen washed with 1N HCl, water, and brine to afford tert-butyl6-((methylsulfonyl)oxy)-2-azaspiro[3.3]heptane-2-carboxylate (324 mg,yield 95%) which was used without further purification.

tert-Butyl 6-((methylsulfonyl)oxy)-2-azaspiro[3.3]heptane-2-carboxylate(324 mg, 1.0 equiv) and NaSMe (160 mg, 2.0 equiv) were combined in DMF(15 mL). The mixture was heated at 60° C. for 4 h. The reaction mixturewas diluted with ethyl acetate (30 mL) and hexane (30 mL), and thenwashed with 3×40 mL water and brine. The crude mixture was purified on asilica gel column to afford tert-butyl6-(methylthio)-2-azaspiro[3.3]heptane-2-carboxylate (144 mg, yield 53%).

tert-Butyl 6-(methylthio)-2-azaspiro[3.3]heptane-2-carboxylate (144 mg,1.0 equiv) was dissolved in DCM (10 mL) and cooled with ice-water.m-CPBA (355 mg, 2.5 equiv) was added. The resulting mixture was stirredat rt for 1 h. The mixture was diluted with DCM (20 mL) and washed with3×30 mL saturated NaHCO₃. The crude mixture was purified on a silica gelcolumn to afford tert-butyl6-(methylsulfonyl)-2-azaspiro[3.3]heptane-2-carboxylate (98 mg, yield60%).

tert-Butyl 6-(methylsulfonyl)-2-azaspiro[3.3]heptane-2-carboxylate wastreated with TFA in DCM (80% v/v) to afford6-(methylsulfonyl)-2-azaspiro[3.3]heptane TFA (Amine Intermediate 20)which was used without purification.

Example BB: Synthesis of 4-((methylsulfonyl)methyl)piperidine TFA (AmineIntermediate 21) and 4-(2-(methylsulfonyl)ethyl)piperidine TFA (AmineIntermediate 22)

Amine Intermediate 21 was synthesized using the methods described inExample AA, using commercially available tert-butyl4-hydroxypiperidine-1-carboxylate in place of tert-butyl6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate.

Amine Intermediate 22 was synthesized using the methods described inExample AA, using commercially available tert-butyl4-(2-hydroxyethyl)piperidine-1-carboxylate in place of tert-butyl6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate.

Example CC: Synthesis of2,3-difluoro-4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-6-isopropyl-[1,1′-biphenyl]-4-carbaldehyde(Aldehyde Intermediate 23) and2-fluoro-4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-6-isopropyl-[1,1′-biphenyl]-4-carbaldehyde(Aldehyde Intermediate 24)

Aldehyde Intermediate 23 was prepared using the methods described inExample H, but substituting 2,3-difluoro-4-hydroxybenzoic acid for2,5-difluoro-4-hydroxybenzoic acid in Step B.

Aldehyde Intermediate 23 was prepared using the methods described inExample H, but substituting 3-fluoro-4-hydroxybenzoic acid for2,5-difluoro-4-hydroxybenzoic acid in Step B.

Example DD: Synthesis of4-ethyl-5-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl)picolinaldehyde(Aldehyde Intermediate 25)

Step A. To a solution of 4-ethylpyridin-2-amine (1 g, 8.2 mmol, 1 equiv)in DCM (30 mL) was added NBS (1.45 g, 8.2 mmol, 1 equiv) at −40° C. Thereaction was stirring at −40° C. for 30 min. The reaction was quenchedwith 50 mL water and extracted with DCM. The organic phase was separatedand concentrated. The residue was purified on a silica gel column(hexane/ethyl acetate) to afford 5-bromo-4-ethylpyridin-2-amine (1.3 g)as a white solid.

Step B. To solution of 5-bromo-4-ethylpyridin-2-amine (1.0 g, 5.0 mmol,1.0 equiv), NaNO₂ (860 mg, 12.5 mmol, 2.5 equiv) in 40% HBr solution (30mL) was added Br₂ (1.8 g, 2.0 equiv) at 0° C. The mixture was thenheated to 70° C. for 2 h. The reaction mixture was poured into DCM (100mL) and water (100 mL). The organic phase was washed with water andsaturated NaHCO₃. The crude product was purified on a silica gel column(hexane/ethyl acetate) to afford 2,5-dibromo-4-ethylpyridine (1.1 g) asa white solid.

Step C. To a solution of 2,5-dibromo-4-ethylpyridine (1 g, 3.8 mmol, 1equiv) in DMF (25 mL) was added CuCN (340 mg, 3.8 mmol, 1 equiv) andNaCN (190 mg, 3.8 mmol, 1 equiv). The mixture was stirred at 150° C. for5 h. After cooling to rt, the reaction mixture was diluted withEtOAc/hexane (8:1, 100 mL) and washed with water, saturated NaHCO₃solution, and water. The organic phase was dried over MgSO₄,concentrated, and purified on a silica gel column to afford5-bromo-4-ethylpicolinonitrile (580 mg) as a white solid.

Step D. To a solution of 5-bromo-4-ethylpicolinonitrile (300 mg, 1.4mmol, 1 equiv) in 1,4-dioxane (10 mL) was added Intermediate 2 fromExample A (570 mg, 1.54 mmol, 1.1 equiv), 2M potassium carbonatesolution (2.1 mL, 4.2 mmol, 3 equiv), and Pd(PPh₃)₄ (80 mg, 0.07 mmol,0.05 equiv). The mixture was degassed and then bubbled with N₂ for 5min. The resulting mixture was stirred at 90° C. for 3 h. Upon coolingto room temperature, the mixture was poured into NH₄Cl solution andextracted with DCM. The organic phase was dried over MgSO₄,concentrated, and purified on a silica gel column to afford4-ethyl-5-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl)picolinonitrile(380 mg) as a white solid.

Step E.4-Ethyl-5-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl)picolinonitrile(200 mg, 0.53 mmol, 1 equiv) was dissolved in 6 N HCl solution. Thereaction was stirred at 100° C. for 3 h, and then concentrated to give4-ethyl-5-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl)picolinicacid which was used without purification.

Step F. To a mixture of4-ethyl-5-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl)picolinicacid (200 mg, 0.5 mmol, 1 equiv), triethylamine (150 mg, 1.5 mmol, 3equiv) and N,O-dimethylhydroxylamine hydrochloride (73 mg, 0.75 mmol,1.5 equiv) in DCM (10 mL) was added HBTU (285 mg, 0.75 mmol, 1.5 equiv).The mixture was stirred at room temperature overnight. The reactionmixture was diluted with DCM (20 mL) and washed with saturated NaHCO₃solution, 2N HCl, and water. The organic phase was dried over MgSO₄ andconcentrated in vacuo to afford4-ethyl-5-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl)-N-methoxy-N-methylpicolinamide(170 mg) as a pale red solid which was used without furtherpurification.

Step G. To a solution of4-ethyl-5-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl)-N-methoxy-N-methylpicolinamide(170 mg, 0.39 mmol, 1 equiv) in anhydrous THF (2 mL) was added 1.0 M LAHsolution in THF (0.39 mL, 1.0 equiv) at −78° C. The reaction was stirredat −78° C. for 1 h and quenched by adding EtOAc before being warmed toroom temperature. The mixture was poured into NH₄Cl solution andextracted with DCM. The organic phase was dried over MgSO₄,concentrated, and purified on a silica gel column to afford AldehydeIntermediate 25 (90 mg) as a white solid.

Example EE: Synthesis of5-ethyl-6-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl)nicotinaldehyde(Aldehyde Intermediate 26)

To a solution of 3-ethylpyridin-2-amine (1.0 g, 8.2 mmol, 1 equiv) in1,4-dioxane (10 mL) and water (2 mL) at 0° C. was added NBS (1.45 g, 8.2mmol, 1 equiv). The resulting mixture was stirring at 0° C. for 2 h. Thereaction was diluted with water (50 mL) and extracted with DCM. Theorganic phase was separated and concentrated. The residue was purifiedon a silica gel column (hexane/EtOAc) to afford5-bromo-3-ethylpyridin-2-amine (1.5 g) as a white solid.

5-bromo-3-ethylpyridin-2-amine (1 g, 1 equiv), Zn(CN)₂ (1.5 equiv) andPdCl₂ (dppf) (10%) were combined in dry DMF (18 mL). The resultingmixture was heated at 120° C. overnight. The reaction mixture was pouredinto DCM (100 mL) and washed with water and saturated NaHCO₃. Theorganic phase was dried over MgSO₄ and concentrated. The residue waspurified on a silica gel column (hexane/EtOAc) to afford6-amino-5-ethylnicotinonitrile (0.7 g) as a white solid.

To a solution of 6-amino-5-ethylnicotinonitrile (0.7 g, 1 equiv) inCH₃CN (15 mL) was added CuCl₂ (2 equiv) and CuCl (2 equiv). To themixture was added n-butyl nitrite (1.3 equiv) at rt. The resultingmixture was stirred at rt for 1 h and then heated at reflux overnight.The reaction mixture was diluted with CH₂Cl₂ and washed with water,saturated NaHCO₃ solution, and water. The organic phase was dried overMgSO₄, concentrated, and purified on a silica gel column to afford6-chloro-5-ethylnicotinonitrile (0.42 g) as a white solid.

6-chloro-5-ethylnicotinonitrile (200 mg, 0.53 mmol, 1 equiv) wasdissolved in 6 N HCl solution. The reaction was stirred at 100° C. for 3h, and then concentrated to give 6-chloro-5-ethylnicotinic acid whichwas used without purification.

To a mixture of 6-chloro-5-ethylnicotinic acid (220 mg, 1 equiv),triethylamine (150 mg, 3 equiv) and N,O-dimethylhydroxylaminehydrochloride (85 mg, 1.5 equiv) in DCM (10 mL) was added HBTU (280 mg,1.4 equiv). The mixture was stirred at room temperature overnight. Thereaction was washed with saturated NaHCO₃ solution, 2N HCl, and water.The organic phase was dried over MgSO₄ and concentrated in vacuo toafford 6-chloro-5-ethyl-N-methoxy-N-methylnicotinamide (150 mg) whichwas used without further purification.

6-Chloro-5-ethyl-N-methoxy-N-methylnicotinamide was substituted for5-bromo-4-ethylpicolinonitrile in the Suzuki coupling reaction describedin Step D of Example DD to provide5-ethyl-6-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl)-N-methoxy-N-methylnicotinamide.5-ethyl-6-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl)-N-methoxy-N-methylnicotinamidewas treated with 1M LAH (1.2 equiv) at −78° C. to afford AldehydeIntermediate 26.

Example FF: Synthesis of2-ethyl-4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2′-methoxy-[1,1′-biphenyl]-4-carbaldehyde(Aldehyde Intermediate 27)

-   -   Aldehyde Intermediate 27

Step A. 4-bromo-3-methoxybenzaldehyde (400 mg, 1.0 equiv) and TMSCF₃(1.5 equiv) was dissolved in dry THF (15 mL), cooled with ice-waterunder N₂. To the mixture was added CsF (1.0 equiv). The mixture wasstirred at rt for 2 h. The reaction was quenched with 1M HCl (30 mL).The mixture was extracted with ethyl acetate and hexane (1:4). The crudemixture was purified on a silica gel column to provide1-(4-bromo-3-methoxyphenyl)-2,2,2-trifluoroethan-1-ol (280 mg).

Step B. 1-(4-Bromo-3-methoxyphenyl)-2,2,2-trifluoroethan-1-ol (200 mg,1.0 equiv) was dissolved in dry DCM (10 mL) and cooled to 0° C. DMP (2.0equiv) was added. The mixture was stirred at rt for 2 h. The crudemixture was purified on a silica gel column to give1-(4-bromo-3-methoxyphenyl)-2,2,2-trifluoroethan-1-one (190 mg).

Step C. To a solution of1-(4-bromo-3-methoxyphenyl)-2,2,2-trifluoroethan-1-one (150 mg, 1.0equiv) and TMSCF₃ (1.5 equiv) in dry THF (8 mL) at 0° C. was added TBAF(1M, 0.1 equiv) dropwise. The mixture was stirred at 0° C. for 20 min,then quenched with 1M HCl (10 mL). The crude mixture was purified on asilica gel column to give2-(4-bromo-3-methoxyphenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (80 mg).

Step D. Preparation of intermediate3-ethyl-N-methoxy-N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide:4-bromo-3-ethylbenzoic acid (5.0 g, 1.0 equiv),N,O-dimethylhydroxylamine hydrochloride (3.2 g, 1.5 equiv) and HBTU (9.6g, 1.15 equiv) were combined in DMF (80 mL) at room temperature. To thereaction mixture was added TEA (11.2 g, 4.0 equiv) dropwise. Theresulting mixture was stirred at rt overnight. The reaction was dilutedwith ethyl acetate (200 mL) and hexane (100 mL), then washed with 2×150mL water, 2×100 mL 1N HCl, 2×100 mL saturated NaHCO₃, and brine. Theorganic phase was dried over MgSO₄ and concentrated in vacuum to provide4-bromo-3-ethyl-N-methoxy-N-methylbenzamide as a pale yellow oil (5.8 g,yield 98%) which was used without further purification.4-Bromo-3-ethyl-N-methoxy-N-methylbenzamide (3.0 g, 1.0 equiv) and4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (3.22 g,1.15 equiv) were dissolved in dry dioxane (25 mL). The mixture wasdegassed by bubbling N₂ for 5 min. PdCl₂(dppf) (0.81 g, 0.1 equiv) andpotassium acetate (1.63 g, 1.5 equiv) were added to reaction mixture.The resulting mixture was heated at 100° C. in a sealed-tube for 15 h.The reaction mixture was diluted with ethyl acetate (80 mL) and hexane(80 mL) and washed with 3×80 mL water and 50 mL brine. The crude mixturewas purified on a silica gel column to afford3-ethyl-N-methoxy-N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(3.34 g, yield 95%) as a pale yellow oil.

Step E. 2-(4-bromo-3-methoxyphenyl)-1,1,1,3,3,3-hexafluoropropan-2-olwas substituted for Intermediate 1 in the Suzuki coupling reactiondescribed in Step C of Example C to provide2-ethyl-4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-N,2′-dimethoxy-N-methyl-[1,1′-biphenyl]-4-.2-ethyl-4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-N,2′-dimethoxy-N-methyl-[1,1′-biphenyl]-4-carboxamidewas treated with 1M LAH (1.2 equiv) at −78° C. to afford AldehydeIntermediate 27.

Example GG: Synthesis of4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2-methoxy-2′-methyl-[1,1′-biphenyl]-4-carbaldehyde(Aldehyde Intermediate 28)

Intermediate 4 was substituted for Intermediate 1 in Step B of Example Ato yield1,1,1,3,3,3-hexafluoro-2-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-ol.

1,1,1,3,3,3-hexafluoro-2-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-olwas substituted for Intermediate 2 and 4-bromo-3-methoxybenzaldehyde wassubstituted for 5-bromo-4-ethylpicolinonitrile in the Suzuki couplingreaction described in Step D of Example DD to yield AldehydeIntermediate 28.

Example HH: Synthesis of3-ethyl-4-(6-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)pyridin-3-yl)benzaldehyde(Aldehyde Intermediate 29)

Methyl 5-bromopicolinate (1.0 g, 1.0 equiv) and TMSCF₃ (6.5 g, 10 equiv)were combined in dry THF (20 mL). The mixture was cooled at 0° C. for 5min. To the solution was added 1M TBAF (23 mL) dropwise over 10 min. Themixture was then stirred at 0° C. for 2 h. The reaction was quenchedwith 1M HCl (50 mL) at 0° C. The mixture was extracted with 3×30 mLhexane. The crude product was purified on a silica gel column to afford2-(5-bromopyridin-2-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol (450 mg).

2-(5-bromopyridin-2-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol wassubstituted for Intermediate 1 in the Suzuki coupling reaction describedin Step C of Example C to provide3-ethyl-4-(6-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)pyridin-3-yl)-N-methoxy-N-methylbenzamide,which was next treated with 1M LAH (1.2 equiv) at −78° C. to affordAldehyde Intermediate 29.

Example II: Synthesis of4-formyl-4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-N,N-dimethyl-[1,1′-biphenyl]-2-carboxamide(Aldehyde Intermediate 30)

Methyl 2-bromo-5-formylbenzoate was substituted for5-bromo-4-ethylpicolinonitrile in the Suzuki coupling reaction describedin Step D of Example DD to provide methyl4-formyl-4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1′-biphenyl]-2-carboxylate.

Methyl4-formyl-4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1′-biphenyl]-2-carboxylatewas treated with solution of LiOH in water and MeOH to provide4-formyl-4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1′-biphenyl]-2-carboxylicacid.4-Formyl-4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1′-biphenyl]-2-carboxylicacid was coupled with N,O-dimethylhydroxylamine hydrochloride in thepresence of HBTU to afford Aldehyde Intermediate 30.

Example JJ: Synthesis of4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-3-hydroxy-[1,1′-biphenyl]-4-carbaldehyde(Aldehyde Intermediate 31)

4-Bromo-2-hydroxybenzaldehyde was substituted for5-bromo-4-ethylpicolinonitrile in the Suzuki coupling reaction describedin Step D of Example DD to provide Aldehyde Intermediate 31.

Example 1: Synthesis of tert-butyl6-((2-ethyl-4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1′-biphenyl]-4-yl)methyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

Commercially available tert-butyl2,6-diazaspiro[3.3]heptane-2-carboxylate as an oxalate salt (62 mg, 1.2equiv) was suspended into 1,2-DCE (15 mL), added Et₃N (26 mg, 2.0 equiv)and stirred at rt for 30 min. Aldehyde Intermediate 5 (80 mg, 1.0 equiv)was added followed by acetic acid (20 μL). The mixture was stirred at rtfor 3 h and NaBH(OAc)₃ (136 mg, 3.0 equiv) was added to the solution.The resulting mixture was stirred at rt overnight. The reaction wasquenched with MeOH, diluted with 20 mL saturated NaHCO₃, and extractedwith 2×20 mL ethyl acetate. The crude mixture was purified on a silicagel column to afford the title compound (65 mg, yield 55%) as a whitesolid. LC-MS (ESI) m z 559.2 (M+H)⁺.

Example 2: Synthesis of2-(2′-ethyl-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol

Amine Intermediate 20 (3.7 g, TFA salt, 1.2 equiv) was suspended into1,2-DCE (50 mL) and to which Aldehyde Intermediate 5 (4.0 g, 1.0 equiv)was added. The mixture was stirred at rt for 3 h. Solid NaBH(OAc)₃ (6.76g, 3.0 equiv) was then added into the reaction. The resulting mixturewas stirred at rt overnight. The reaction was quenched with MeOH (10 mL)and washed with saturated NaHCO₃, water, and brine. The crude mixturewas purified on a silica gel column to afford the title product (3.5 g,yield 61.4%) as a white solid. LC-MS (ESI) m z 537.4 (M+H)⁺.

Example 3: Synthesis of2-((2-ethyl-4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1′-biphenyl]-4-yl)methyl)-7-thia-2-azaspiro[3.5]nonane7,7-dioxide

7-Thia-2-azaspiro[3.5]nonane 7,7-dioxide (50 mg, 1.2 equiv) and AldehydeIntermediate 5 (90 mg, 1.0 equiv) were combined in 1,2-DCE (25 mL). Tothe mixture was added acetic acid (40 μL). The reaction mixture wasstirred at rt for 3 h. NaBH(OAc)₃ (155 mg, 3.0 equiv) was added. Theresulting mixture was stirred at rt overnight. The reaction was quenchedwith MeOH, washed with saturated NaHCO₃, and extracted with 2×20 mL DCM.The crude mixture was purified on a silica gel column to afford thetitle compound (28 mg, yield 22%). LC-MS (ESI) m z 536.4 (M+H)⁺.

Example 4: Synthesis of2-(2′-ethyl-4′-((2-(methylsulfonyl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol

tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate (100 mg, 1.2 equiv)and aldehyde intermediate 5 (85 mg, 1.0 equiv) were combined in 1,2-DCE(15 mL). To the mixture was added acetic acid (20 μL). The reactionmixture was stirred at rt for 3 h. NaBH(OAc)₃ (145 mg, 3.0 equiv) wasadded. The resulting mixture was stirred at rt overnight. The reactionwas quenched with MeOH, washed with saturated NaHCO₃, and extracted with2×20 mL DCM. The crude mixture was purified on a silica gel column toafford tert-butyl7-((2-ethyl-4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1′-biphenyl]-4-yl)methyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate(103 mg, yield 78%).

tert-Butyl7-((2-ethyl-4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1′-biphenyl]-4-yl)methyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate(103 mg) was treated with 4 mL (80% TFA in DCM) for 1 h. The solvent wasremoved in vacuo to afford2-(4′-((2,7-diazaspiro[3.5]nonan-7-yl)methyl)-2′-ethyl-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol(106 mg) as a TFA salt which was used without purification.

2-(4′-((2,7-Diazaspiro[3.5]nonan-7-yl)methyl)-2′-ethyl-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-olTFA salt (53 mg) was suspended in DCM (10 mL) and saturated NaHCO₃ (5mL) was added. To the mixture was added MsCl (3.0 equiv) in DCM (5 mL)dropwise over 20 min at 0° C. The resulting mixture was stirred at rtfor 2 h. The mixture was washed with water and brine. The crude productwas purified on a silica gel column to afford the title compound (25 mg,yield 51%). LC-MS (ESI) m z 565.6 (M+H)⁺.

Example 5: Synthesis of2-(2′-ethyl-4′-((2-(methylsulfonyl)-2,6-diazaspiro[3.5]nonan-6-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol

The title compound was made using the method described in Example 4, butsubstituting tert-butyl 2,6-diazaspiro[3.5]nonane-2-carboxylate fortert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate. LC-MS (ESI) m z565.5 (M+H)⁺.

Example 6: Synthesis of2-(2′-ethyl-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.4]octan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol

The title compound was made using the method described in Example 4, butsubstituting tert-butyl 2,6-diazaspiro[3.4]octane-2-carboxylate fortert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate. LC-MS (ESI) m z551.4 (M+H)⁺.

Examples 7-61

The following compounds in Table 1 were synthesized using the proceduresdescribed in the preceding examples wherein an aldehyde intermediate(Aldehyde Int.) (1.0 equiv) and an amine intermediate (Amine Int.) (1.2equiv) were combined to afford the title compounds.

TABLE 1 LC-MS Ex. Intermediates (ESI) m/z No. Structure Chemical Nameused (M + H)⁺  7

2-(3′,6′-difluoro-2′-isopropyl-4′-((6- (methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)- [1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol Aldehyde Int. 11 Amine Int. 2 587.2  8

2-(3′,5′-difluoro-2′-isopropyl-4′-((6- (methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)- [1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol Aldehyde Int. 12 Amine Int. 2 587.4  9

2-(2′-ethyl-4′-((4- ((methylsulfonyl)methyl)piperidin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)- 1,1,1,3,3,3-hexafluoropropan-2-olAldehyde Int. 5 Amine Int. 21 538.5 10

2-(2′-ethyl-4′-((4- (methylsulfonyl)piperidin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)- 1,1,1,3,3,3-hexafluoropropan-2-olAldehyde Int. 5 Amine Int. 21 524.4 11

6-((4′-(1,1,1,3,3,3-hexafluoro-2- hydroxypropan-2-yl)-2-isopropyl-2′-methyl-[1,1′-biphenyl]-4-yl)methyl)- 2-thia-6-azaspiro[3.4]octane 2,2-dioxide Aldehyde Int. 20 Commercially available 2-thia- 6-azaspiro[3.4]octane 2,2- dioxide 550.5 12

6-((4′-(1,1,1,3,3,3-hexafluoro-2- hydroxypropan-2-yl)-2-isopropyl-2′-methyl-[1,1′-biphenyl]-4-yl)methyl)- 2-thia-6-azaspiro[3.3]heptane 2,2-dioxide Aldehyde Int. 20 Amine Int. 11 536.4 13

2-(2′-(sec-butyl)-4′-((6- (methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)- [1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol Aldehyde Int. 10 Amine Int. 2 565.5 14

2-(2′,3′-difluoro-6′-isopropyl-4′-((6- (methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)- [1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol Aldehyde Int. 23 Amine Int. 2 587.3 15

1,1,1,3,3,3-hexafluoro-2-(2′-fluoro-6′-isopropyl-4′-((6-(methylsulfonyl)- 2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4- yl)propan-2-ol Aldehyde Int. 24 Amine Int.2 569.4 16

6-((2-ethyl-4′-(1,1,1,3,3,3- hexafluoro-2-hydroxypropan-2-yl)-2′-methyl-[1,1′-biphenyl]-4- yl)methyl)-2-thia-6- azaspiro[3.4]octane2,2-dioxide Aldehyde Int. 22 Commercially available 2-thia-6-azaspiro[3.4] octane 2,2- dioxide 536.5 17

6-((2-ethyl-4′-(1,1,1,3,3,3- hexafluoro-2-hydroxypropan-2-yl)-[1,1′-biphenyl]-4-yl)methyl)-2-thia- 6-azaspiro[3.4]octane 2,2-dioxideAldehyde Int. 5 Commercially available 2-thia- 6-azaspiro[3.4] octane2,2- dioxide 522.4 18

6-((2-ethyl-4′-(1,1,1,3,3,3- hexafluoro-2-hydroxypropan-2-yl)-2′-methyl-[1,1′-biphenyl]-4- yl)methyl)-2-thia-6- azaspiro[3.3]heptane2,2-dioxide Aldehyde Int. 22 Amine Int. 11 522.5 19

2-(2′-ethyl-4′-((6-(methylsulfonyl)- 2,6-diazaspiro[3.5]nonan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)- 1,1,1,3,3,3-hexafluoropropan-2-olAldehyde Int. 5 Amine Int. 17 565.6 20

2-(2′-ethyl-4′-((6-(isobutylsulfonyl)- 2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)- 1,1,1,3,3,3-hexafluoropropan-2-olAldehyde Int. 5 Amine Int. 6 579.6 21

2-(2′-ethyl-4′-((6-(propylsulfonyl)- 2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)- 1,1,1,3,3,3-hexafluoropropan-2-olAldehyde Int. 5 Amine Int. 5 565.6 22

2-(2′-ethyl-4′-((6-(ethylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)- [1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol Aldehyde Int. 5 Amine Int. 3 551.5 23

2-(2′-(tert-butyl)-4′-((6- (methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)- [1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol Aldehyde Int. 13 Amine Int. 2 565.4 24

2-((2-ethyl-4′-(1,1,1,3,3,3- hexafluoro-2-hydroxypropan-2-yl)-[1,1′-biphenyl]-4-yl)methyl)-6-thia- 2-azaspiro[3.4]octane 6,6-dioxideAldehyde Int. 5 Amine Int. 12 522.5 25

2-((2-ethyl-4′-(1,1,1,3,3,3- hexafluoro-2-hydroxypropan-2-yl)-[1,1′-biphenyl]-4-yl)methyl)-6-thia- 2-azaspiro[3.4]octane 6-oxideAldehyde Int. 5 Amine Int. 10 506.3 26

6-((2-ethyl-4′-(1,1,1,3,3,3- hexafluoro-2-hydroxypropan-2-yl)-[1,1′-biphenyl]-4-yl)methyl)-2-thia- 6-azaspiro[3.3]heptane 2,2-dioxideAldehyde Int. 5 Amine Int. 11 508.2 27

6-((2-ethyl-4′-(1,1,1,3,3,3- hexafluoro-2-hydroxypropan-2-yl)-[1,1′-biphenyl]-4-yl)methyl)-2-thia- 6-azaspiro[3.3]heptane 2-oxideAldehyde Int. 5 Amine Int. 9 492.3 28

2-(4′-((2-thia-6-azaspiro[3.3]heptan-6-yl)methyl)-2′-ethyl-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan- 2-ol Aldehyde Int. 5 Commerciallyavailable 2-thia- 6-azaspiro[3.3] heptane 476.3 29

N-((l-((2-ethyl-4′-(1,1,1,3,3,3- hexafluoro-2-hydroxypropan-2-yl)-[1,1′-biphenyl]-4-yl)methyl)azetidin- 3-yl)methyl)-N-methylmethanesulfonamide Aldehyde Int. 5 Amine Int. 14 539.6 30

2-(2′-ethyl-4′-((2-(methylsulfonyl)- 2,6-diazaspiro[3.4]octan-6-yl)methyl)-[1,1′-biphenyl]-4-yl)- 1,1,1,3,3,3-hexafluoropropan-2-olAldehyde Int. 5 Amine Int. 15 551.6 31

2-(2′-ethyl-4′-((7-(methylsulfonyl)- 2,7-diazaspiro[4.4]nonan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)- 1,1,1,3,3,3-hexafluoropropan-2-olAldehyde Int. 5 Amine Int. 19 565.6 32

N-((1-((2-ethyl-4′-(1,1,1,3,3,3- hexafluoro-2-hydroxypropan-2-yl)-[1,1′-biphenyl]-4-yl)methyl)azetidin- 3-yl)methyl)methanesulfonamideAldehyde Int. 5 Amine Int. 13 525.6 33

2-(2′-ethyl-4′-((7-(methylsulfonyl)- 2,7-diazaspiro[3.5]nonan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)- 1,1,1,3,3,3-hexafluoropropan-2-olAldehyde Int. 5 Amine Int. 16 565.7 34

2-(2′-ethyl-2-fluoro-4′-((6- (methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)- [1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol Aldehyde Int. 21 Amine Int. 2 555.2 35

2-(2′-ethyl-6′-fluoro-4′-((6- (methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)- [1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol Aldehyde Int. 6 Amine Int. 2 555.3 36

2-(2′-ethyl-5′-fluoro-4′-((6- (methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)- [1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol Aldehyde Int. 7 Amine Int. 2 555.3 37

2-(2′-ethyl-3′-fluoro-4′-((6- (methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)- [1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol Aldehyde Int. 8 Amine Int. 2 555.3 38

tert-butyl 2-((2-ethyl-4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)- [1,1′-biphenyl]-4-yl)methyl)-2,6-diazaspiro[3.4]octane-6-carboxylate Aldehyde Int. 5 Commerciallyavailable tert-butyl 2,6- diazaspiro[3.4] octane- 6-carboxylate 573.4 39

2-(2′-ethyl-2-methyl-4′-((6- (methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)- [1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol Aldehyde Int. 22 Amine Int. 2 551.3 40

methyl 6-((2-ethyl-4′-(1,1,1,3,3,3- hexafluoro-2-hydroxypropan-2-yl)-[1,1′-biphenyl]-4-yl)methyl)-2,6- diazaspiro[3.3]heptane-2-carboxylateAldehyde Int. 5 Amine Int. 8 517.5 41

2-(4′-((6-(cyclopropylsulfonyl)-2,6- diazaspiro[3.3]heptan-2-yl)methyl)-2′-ethyl-[1,1′-biphenyl]-4-yl)- 1,1,1,3,3,3-hexafluoropropan-2-olAldehyde Int. 5 Amine Int. 4 563.6 42

2-(2′-cyclopropyl-4′-((6- (methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)- [1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol Aldehyde Int. 19 Amine Int. 2 549.2 43

1,1,1,3,3,3-hexafluoro-2-(2′- isopropyl-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2- yl)methyl)-[1,1′-biphenyl]-4-yl)propan-2-ol Aldehyde Int. 20 Amine Int. 2 551.5 44

1,1,1,3,3,3-hexafluoro-2-(4′-((6- (methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-2′-(prop-1-en-2-yl)-[1,1′-biphenyl]-4- yl)propan-2-ol Aldehyde Int. 18Amine Int. 2 549.2 45

2-(2′-bromo-4′-((6-(methylsulfonyl)- 2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)- 1,1,1,3,3,3-hexafluoropropan-2-olAldehyde Int. 17 Amine Int. 2 587,589 (1:1) 46

1,1,1,3,3,3-hexafluoro-2-(4′-((6- (methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-2′-(trifluoromethyl)-[1,1′-biphenyl]- 4-yl)propan-2-ol Aldehyde Int. 16Amine Int. 2 577.3 47

2-(2′-chloro-4′-((6-(methylsulfonyl)- 2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)- 1,1,1,3,3,3-hexafluoropropan-2-olAldehyde Int. 15 Amine Int. 2 543,545 (3:1) 48

1-(6-((2-ethyl-4′-(1,1,1,3,3,3- hexafluoro-2-hydroxypropan-2-yl)-[1,1′-biphenyl]-4-yl)methyl)-2,6- diazaspiro[3.3]heptan-2-yl)ethan-1-one Aldehyde Int. 5 Amine Int. 7 501.2 49

1-(6-((4′-(1,1,1,3,3,3-hexafluoro-2- hydroxypropan-2-yl)-2-methyl-[1,1′-biphenyl]-4-yl)methyl)-2,6- diazaspiro[3.3]heptan-2-yl)ethan-1- oneAldehyde Int. 14 Amine Int. 7 487.3 50

1,1,1,3,3,3-hexafluoro-2-(2′-methyl- 4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)- [1,1′-biphenyl]-4-yl)propan-2-olAldehyde Int. 14 Amine Int. 2 523.6 51

1,1,1,3,3,3-hexafluoro-2-(2′-methyl- 4′-((6-(pyridin-4-ylmethyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)- [1,1′-biphenyl]-4-yl)propan-2-olAldehyde Int. 14 Amine Int. 1 536.3 52

2-(4-(3-ethyl-5-((6-(methylsulfonyl)- 2,6-diazaspiro[3.3]heptan-2-yl)methyl)pyridin-2-yl)phenyl)- 1,1,1,3,3,3-hexafluoropropan-2-olAldehyde Int. 26 Amine Int. 2 538.3 53

7-((2-ethyl-4′-(1,1,1,3,3,3- hexafluoro-2-hydroxypropan-2-yl)-[1,1′-biphenyl]-4-yl)methyl)-2,7- diazaspiro[4.4]nonan-1-one AldehydeInt. 5 Commercially available 2,7- diazaspiro[4.4] nonan-1-one 501.3 54

7-((2-ethyl-4′-(1,1,1,3,3,3- hexafluoro-2-hydroxypropan-2-yl)-[1,1′-biphenyl]-4-yl)methyl)-2,7- diazaspiro[4.4]nonan-3-one AldehydeInt. 5 Commercially available 2,7- diazaspiro[4.4] nonan-3-one 501.3 55

4′-(1,1,1,3,3,3-hexafluoro-2- hydroxypropan-2-yl)-N,N-dimethyl-4-((6-(methylsulfonyl)-2,6- diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-2-carboxamide Aldehyde Int. 30 Amine Int. 2 580.3 56

2-(2′-ethyl-2-methoxy-4′-((6- (methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)- [1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol Aldehyde Int. 27 Amine Int. 2 567.5

LC-MS Ex. Intermediates (ESI) m/z No. Structure Chemical Name used (M +H)⁺ 57

1,1,1,3,3,3-hexafluoro-2-(2′- methoxy-2-methyl-4′-((6-(methylsulfonyl)-2,6- diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)propan-2-ol Aldehyde Int. 28 Amine Int. 2 553.5 58

7-((2-ethyl-4′-(1,1,1,3,3,3- hexafluoro-2-hydroxypropan-2-yl)-[1,1′-biphenyl]-4-yl)methyl)-2-thia- 7-azaspiro[4.4]nonane 2,2-dioxideAldehyde Int. 5 Commercially available 2-thia- 7-azaspiro[4.4] nonane2,2-dioxide 536.3 59

2-(5-(2-ethyl-4-((6-(methylsulfonyl)- 2,6-diazaspiro[3.3]heptan-2-yl)methyl)phenyl)pyridin-2-yl)- 1,1,1,3,3,3-hexafluoropropan-2-olAldehyde Int. 29 Amine Int. 2 538.4 60

2-(4-(4-ethyl-6-((6-(methylsulfonyl)- 2,6-diazaspiro[3.3]heptan-2-yl)methyl)pyridin-3-yl)phenyl)- 1,1,1,3,3,3-hexafluoropropan-2-olAldehyde Int. 25 Amine Int. 2 538.4 61

4′-(1,1,1,3,3,3-hexafluoro-2- hydroxypropan-2-yl)-4-((6-(methylsulfonyl)-2,6- diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-3-ol Aldehyde Int. 31 Amine Int. 2 525.4

Example 62: Synthesis of2-(4-(3-ethyl-5-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)pyridin-2-yl)-3-methylphenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol

To a solution of 3-ethylpyridin-2-amine (1 g, 8.2 mmol, 1 equiv) in1,4-dioxane (10 mL) and water (2 mL) at 0° C. was added NBS (1.45 g, 8.2mmol, 1 equiv). The resulting mixture was stirred at 0° C. for 2 h. Thereaction was diluted with water (50 mL) and extracted with DCM. Theorganic phase was separated and concentrated. The residue was purifiedon a silica gel column (hexane/ethyl acetate) to afford5-bromo-3-ethylpyridin-2-amine (1.5 g) as a white solid.

5-Bromo-3-ethylpyridin-2-amine (1 g, 1 equiv), Zn(CN)₂ (1.5 equiv) andPdCl₂(dppf) (10%) were combined in dry DMF (18 mL). The resultingmixture was heated to 120° C. overnight. The reaction mixture was pouredinto DCM (100 mL) and washed with water and saturated NaHCO₃. Theorganic phase was dried over MgSO₄ and concentrated. The residue waspurified on a silica gel column (hexane/ethyl acetate) to afford6-amino-5-ethylnicotinonitrile (0.7 g) as a white solid.

To a solution of 6-amino-5-ethylnicotinonitrile (0.7 g, 1 equiv) inCH₃CN (15 mL) was added CuCl₂ (2 equiv) and CuCl (2 equiv). To themixture was added n-butyl nitrite (1.3 equiv) at rt. The resultingmixture was stirred at rt for 1 h and then heated at reflux overnight.The reaction mixture was diluted with CH₂Cl₂ and washed with water,saturated NaHCO₃ solution, and water. The organic phase was dried overMgSO₄, concentrated, and purified on a silica gel column to afford6-chloro-5-ethylnicotinonitrile (0.42 g) as a white solid.

6-Chloro-5-ethylnicotinonitrile (200 mg, 0.53 mmol, 1 equiv) wasdissolved in 6 N HCl solution. The reaction was stirred at 100° C. for 3h and then concentrated to give 6-chloro-5-ethylnicotinic acid which wasused without purification.

To a mixture of 6-chloro-5-ethylnicotinic acid (220 mg, 1 equiv),triethylamine (150 mg, 3 equiv) and N,O-dimethylhydroxylaminehydrochloride (85 mg, 1.5 equiv) in DCM (10 mL) was added HBTU (280 mg,1.4 equiv). The mixture was stirred at room temperature overnight. Thereaction was washed with saturated NaHCO₃ solution, 2N HCl, and water.The organic phase was dried over MgSO₄, and concentrated in vacuo toafford 6-chloro-5-ethyl-N-methoxy-N-methylnicotinamide (150 mg) whichwas used without further purification.

6-Chloro-5-ethyl-N-methoxy-N-methylnicotinamide applied standard Suzukicoupling with1,1,1,3,3,3-hexafluoro-2-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-olto provide5-ethyl-6-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2-methylphenyl)-N-methoxy-N-methylnicotinamide.5-Ethyl-6-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2-methylphenyl)-N-methoxy-N-methylnicotinamide(Compound 7) was treated with 1M LAH (1.2 equiv) at −78° C. to affordthe aldehyde intermediate5-ethyl-6-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2-methylphenyl)nicotinaldehyde.

The title compound was made using the reductive amination proceduredescribed in the general procedure with the aldehyde intermediate fromthe previous step and Amine intermediate 2 from Example Q.

Example 63: Synthesis of2-(6-(2-ethyl-4-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)phenyl)pyridin-3-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol

To a solution of methyl 6-bromonicotinate (1.0 equiv) in THF (20 mL) wasadded TMSCF₃ (5.0 equiv). The mixture was cooled at −15° C. To themixture was added 1M TBAF in THF (3.0 equiv) dropwise for over 20 min.After addition of TMSCF₃, saturated NH₄Cl (50 mL) was added slowly. Themixture was stirred at rt for 15 min and extracted with 2×40 mL hexane.The organic phase was dried over MgSO₄ and concentrated in vacuum toafford 1-(6-bromopyridin-3-yl)-2,2,2-trifluoroethan-1-one which was usedin the next step without purification.

1-(6-Bromopyridin-3-yl)-2,2,2-trifluoroethan-1-one and TMSCF₃ (5.0equiv) was dissolved in THF (20 mL) and cooled to 0° C. TBAF (1M, 5 mL)was added dropwise. The resulting mixture was stirred at 0° C. for 2 h.The reaction was quenched with saturated NH₄Cl (80 mL). The mixture wasextracted with 2×40 mL hexane. The crude mixture was purified on asilica gel column to afford2-(6-bromopyridin-3-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol.

2-(6-Bromopyridin-3-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol wassubstituted for Intermediate 1 in the Suzuki coupling reaction describedin Step C of Example C to afford3-ethyl-4-(5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)pyridin-2-yl)-N-methoxy-N-methylbenzamide.3-Ethyl-4-(5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)pyridin-2-yl)-N-methoxy-N-methylbenzamidewas reduced to3-ethyl-4-(5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)pyridin-2-yl)benzaldehydeby LAH.

The title compound was made using the reductive amination proceduredescribed in the general procedure with the aldehyde intermediate fromthe previous step and Amine Intermediate 2 from Example Q.

Example 64: Synthesis of2-(4-(4-ethyl-6-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)pyridin-3-yl)-3-methylphenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol

Commercially available 5-bromo-4-ethylpicolinaldehyde (1.0 equiv) and2-(methylsulfonyl)-2,6-diazaspiro[3.3]heptane (Amine Intermediate 2)(1.2 equiv) were combined into 1,2-DCE (3 mL), the mixture was stirredat rt for 2 h, then NaBH(OAc)₃ (2.5 equiv) was added.

The resulting mixture was stirred at rt overnight. Regular work up andpurification on a silica gel column afforded2-((5-bromo-4-ethylpyridin-2-yl)methyl)-6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptane.

Standard Suzuki coupling between2-((5-bromo-4-ethylpyridin-2-yl)methyl)-6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptaneand1,1,1,3,3,3-hexafluoro-2-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-olunder the conditions described in Step A of Example K afforded the titlecompound.

Example 65: Synthesis of2′-ethyl-4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-2-carbonitrile

Step A. Synthesis of3-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehydeIntermediate. 4-Bromo-3-ethylbenzoic acid (5.0 g, 1.0 equiv),N,O-dimethylhydroxylamine hydrochloride (3.2 g, 1.5 equiv) and HBTU (9.6g, 1.15 equiv) were combined in DMF (80 mL) at room temperature. To thereaction mixture was added TEA (11.2 g, 4.0 equiv) dropwise. Theresulting mixture was stirred at rt overnight. The reaction was dilutedwith ethyl acetate (200 mL) and hexane (100 mL), then washed with 2×150mL water, 2×100 mL 1N HCl, 2×100 mL saturated NaHCO₃, and brine. Theorganic phase was dried over MgSO₄ and concentrated in vacuum to provide4-bromo-3-ethyl-N-methoxy-N-methylbenzamide (5.8 g, yield 98%) as a paleyellow oil which was used without further purification.

4-Bromo-3-ethyl-N-methoxy-N-methylbenzamide (1.0 equiv) was dissolved indry THF and cooled to −50° C. To the solution was added 1M LAH in THF(0.6 equiv). The reaction was stirred at −30° C. for 1 h and thenquenched with 1N HCl at −10° C. to afford 4-bromo-3-ethylbenzaldehydewhich was used without purification.

4-Bromo-3-ethylbenzaldehyde (1.0 equiv) and4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1.15 equiv)were dissolved in dry toluene (25 mL). The mixture was degassed bybubbling N₂ for 5 min. PdCl₂(dppf) (0.1 equiv) and potassium acetate(1.5 equiv) were added to reaction mixture. The resulting mixture washeated at 100° C. in a sealed-tube for 15 h. The reaction mixture wasdried in vacuum. The crude mixture was purified on a silica gel columnto afford3-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde.

Step B. Synthesis of2-bromo-5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzonitrileIntermediate: 2-Bromo-5-formylbenzonitrile (1.0 equiv) was dissolved inTHF to which was added TMSCF₃ (2.0 equiv) and the mixture was cooled to0° C. To the mixture was added CsF (0.3 equiv). The resulting mixturewas stirred at 0° C. for 30 min and then at rt 1 h. To the mixture wasadded 1M TBAF (2.0 equiv). The reaction was then quenched with saturatedNH₄Cl (50 mL) and extracted with 2×40 mL hexane. The organic phase wasdried over MgSO₄ and concentrated in vacuum to afford oil2-bromo-5-(2,2,2-trifluoro-1-hydroxyethyl)benzonitrile which was usedwithout purification.

2-Bromo-5-(2,2,2-trifluoro-1-hydroxyethyl)benzonitrile was dissolved inDCM, then DMP (1.5 equiv) was added at rt. The mixture was stirred at rtfor 1 h and then quenched with saturated NaHCO₃. The crude mixture waspurified on a silica gel column to afford2-bromo-5-(2,2,2-trifluoroacetyl)benzonitrile.

2-Bromo-5-(2,2,2-trifluoroacetyl)benzonitrile and TMSCF₃ (2.0 equiv) wasdissolved in anhydride THF (20 mL) and cooled to 0° C. 1M TBAF in THF(1.0 equiv) was added dropwise. The resulting mixture was stirred at 0°C. for 2 h. The reaction was quenched with saturated NH₄Cl (80 mL). Themixture was extracted with 2×40 mL hexane. The crude mixture waspurified on a silica gel column to afford2-bromo-5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzonitrile.

Step C: Synthesis of Aldehyde Intermediate. Suzuki coupling between2-bromo-5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzonitrile fromthe previous step with3-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde fromStep A under reaction conditions described in Step A of Example K,afforded the aldehyde intermediate2′-ethyl-4′-formyl-4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1′-biphenyl]-2-carbonitrile.

Step D: The title compound was made using the reductive aminationprocedure described in the general procedure with the aldehydeintermediate from Step C and Amine Intermediate 2 from Example Q.

Example 66: Synthesis of2-(2,2′-dimethyl-3′-(6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol

1,3-Dibromo-2-methylbenzene (1.2 equiv) and tert-butyl2,6-diazaspiro[3.3]heptane-2-carboxylate oxalic acid (1.0 equiv) weresuspended in 5 mL dry toluene, to which was added Pd₂(dba)₃ (0.05equiv), RuPhos (0.1 equiv) and sodium t-butyloxide (2.5 equiv). Themixture was bubbled with N₂ for 5 min. The resulting mixture was heatedat 100° C. for 5 h. The solvent was removed in high vacuum. The residuewas purified on a silica gel column to afford tert-butyl6-(3-bromo-2-methylphenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate.

tert-Butyl6-(3-bromo-2-methylphenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate fromthe previous step was treated with 50% TFA in DCM to provide thecorresponding amine as a TFA salt. The TFA salt amine was suspended intoDCM and water, adjusted to pH>10 by adding 2M K₂CO₃. The mixture wascooled to 0° C. and MsCl (2.0 equiv) was added. The mixture was stirredat rt for 2 h. The crude mixture was purified on a silica gel column toafford2-(3-bromo-2-methylphenyl)-6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptane.

Standard Suzuki coupling between2-(3-bromo-2-methylphenyl)-6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptaneand Intermediate 2A under reaction conditions described in Step A ofExample K afforded the title compound.

Example 67: Synthesis of1,1,1,3,3,3-hexafluoro-2-(3-methyl-4-(6-(6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)phenyl)propan-2-ol

The title compound was prepared using the procedure described in Example66, but substituting 2,6-dibromopyridine for 1,3-dibromo-2-methylbenzenein the first step.

Example 68: Synthesis of2-(2′-ethyl-3′,6′-difluoro-2-methyl-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol

Step A. 2,5-difluoro-4-methoxybenzoic acid (500 mg) was treated withBBr₃ at room temperature for 24 h. The reaction was worked up with 2NHCl, and purified on a silica gel column to give2,5-difluoro-4-hydroxybenzoic acid.

Step B. To a mixture of 2,5-difluoro-4-hydroxybenzoic acid (1 equiv),triethylamine (3 equiv) and N,O-dimethylhydroxylamine hydrochloride (10equiv) in DCM (20 mL) was added HBTU (2.5 equiv). The mixture wasstirred at room temperature overnight. The mixture was washed with 2NHCl and water. The organic phase was dried over MgSO₄, concentrated, andpurified on a silica gel column to afford2,5-difluoro-4-hydroxy-N-methoxy-N-methylbenzamide as a colorless oil.

Step C. To a solution of2,5-difluoro-4-hydroxy-N-methoxy-N-methylbenzamide (1.0 equiv) in aceticacid (4 mL) was added NBS (1.1 equiv) at 0° C. The reaction mixture waswarmed to room temperature and stirred for 2 h. The solvent was removedunder reduced pressure. The residue was dissolved in EtOAc, washed withwater, concentrated, and purified on a silica gel column to afford3-bromo-2,5-difluoro-4-hydroxy-N-methoxy-N-methylbenzamide as a whitesolid.

Step D. To a solution of3-bromo-2,5-difluoro-4-hydroxy-N-methoxy-N-methylbenzamide (1 equiv) in1,4-dioxane (5 mL) was added4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (1.5 equiv), 2Mpotassium carbonate solution (3 equiv), and Pd(PPh₃)₄ (0.05 equiv). Themixture was degassed and then bubbled with N₂ for 5 min, and thenstirred at 90° C. overnight. Upon cooling to room temperature, themixture was poured into NH₄Cl solution and extracted with DCM. Theorganic phase was dried over MgSO₄, concentrated, and purified on asilica gel column to afford2,5-difluoro-4-hydroxy-N-methoxy-N-methyl-3-vinylbenzamide as a whitesolid.

Step E. To a mixture of2,5-difluoro-4-hydroxy-N-methoxy-N-methyl-3-vinylbenzamide (1.0 equiv)and pyridine (0.5 mL) in DCM (10 mL) was added trifluoromethanesulfonicanhydride (1.5 equiv) dropwise at 0° C. The mixture was stirred at 0° C.for 1 h, and washed with saturated NaHCO₃ solution, and water. Theorganic phase was dried over MgSO₄, concentrated, and purified on asilica gel column to afford3,6-difluoro-4-(methoxy(methyl)carbamoyl)-2-vinylphenyltrifluoromethanesulfonate as a pale yellow oil.

Step F. To a solution of3,6-difluoro-4-(methoxy(methyl)carbamoyl)-2-vinylphenyltrifluoromethanesulfonate (1.0 equiv) in anhydrous 1,4-dioxane (10 mL)was added Intermediate 2A from Example A (1.5 equiv), 2M potassiumcarbonate solution (3 equiv), and Pd(PPh₃)₄ (0.05 equiv). The mixturewas degassed and then bubbled with N₂ for 5 min, and then stirred at 90°C. overnight. Upon cooling to room temperature, the mixture was pouredinto NH₄Cl solution and extracted with DCM. The organic phase was driedover MgSO₄, concentrated, and purified on a silica gel column to afford3,6-difluoro-4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-N-methoxy-N-methyl-2-vinyl-[1,1′-biphenyl]-4-carboxamideas a white solid.

Step G. To a solution of3,6-difluoro-4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-N-methoxy-N-methyl-2-vinyl-[1,1′-biphenyl]-4-carboxamide(1.0 equiv) in MeOH (10 mL) was added Pd/C (10% wt.). The reaction wasshaken under H₂ (50 psi) environment for 4 h. The mixture was filteredto remove the catalyst and concentrated to afford2-ethyl-3,6-difluoro-4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-N-methoxy-N-methyl-[1,1′-biphenyl]-4-carboxamideas a white solid.

Step H. To a solution of2-ethyl-3,6-difluoro-4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-N-methoxy-N-methyl-[1,1′-biphenyl]-4-carboxamide(120 mg, 0.25 mmol, 1 equiv) in anhydrous THF (2 mL) was added 1.0 M LAHsolution in THF (1.0 equiv) at −78° C. The reaction was stirred at −78°C. for 1 h and quenched by adding EtOAc before being warmed to roomtemperature. The mixture was poured into NH₄Cl solution and extractedwith DCM. The organic phase was dried over MgSO₄, concentrated, andpurified on a silica gel column to afford2-ethyl-3,6-difluoro-4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1′-biphenyl]-4-carbaldehydeas a white solid.

Step I. The title compound was made using the reductive aminationprocedure described in the general procedure with the aldehydeintermediate from the previous step and Amine intermediate 2 fromExample Q.

Example 69: Synthesis of2-(2′-ethyl-3′,6′-difluoro-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol

The title compound was prepared as described in Example 68, substitutingIntermediate 2 for Intermediate 2A in Step F.

Example 70: Synthesis of2-(2′-ethyl-2,3′,6′-trifluoro-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol

The title compound was prepared as described in Example 68, substitutingIntermediate 2B for Intermediate 2A in Step F.

Example 71: Synthesis of2-(2,2′-diethyl-3′,6′-difluoro-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol

The title compound was prepared as described in Example 68 substitutingIntermediate 2C for Intermediate 2A in Step F.

Example 72: Synthesis of2-(2-chloro-2′-ethyl-3′,6′-difluoro-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol

The title compound was prepared as described in Example 68, substitutingIntermediate 2D for Intermediate 2A in Step F.

Example 73: Synthesis of2-(4-(2-ethyl-6-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)pyridin-3-yl)-3-methylphenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol

5-bromo-6-ethylpicolinaldehyde (1.0 equiv) and Amine Intermediate 2 fromExample Q 1.2 equiv) were combined into 1,2-DCE (3 mL). The mixture wasstirred at rt for 2 h and then NaBH(OAc)₃ (2.5 equiv) was added. Theresulting mixture was stirred at rt overnight. Regular work up andpurification on a silica gel column afforded2-((5-bromo-6-ethylpyridin-2-yl)methyl)-6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptane.

Standard Suzuki coupling between2-((5-bromo-6-ethylpyridin-2-yl)methyl)-6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptaneand Intermediate 2A from Example A under conditions described in Step Aof Example K afforded2-(4-(2-ethyl-6-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)pyridin-3-yl)-3-methylphenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol.

Example 74: Synthesis of2-(3′,6′-difluoro-2′-isopropyl-4′-((2-(methylsulfonyl)-2,6-diazaspiro[3.4]octan-6-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol

The title compound was made using the reductive amination proceduredescribed in the general procedure with Aldehyde Intermediate 11 fromExample H and Amine Intermediate 15 from Example W.

Example 75: Synthesis of2-(2-chloro-2′-ethyl-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol

The title compound was made using the procedure described in Example 65but substituting 4-bromo-3-chlorobenzaldehyde for2-bromo-5-formylbenzonitrile in Step A.

Example 76: Synthesis of2-(2-ethyl-2′-methyl-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol

The title compound was prepared using the procedure described in Steps Band C of Example 65, but substituting 4-bromo-3-ethylbenzaldehyde for2-bromo-5-formylbenzonitrile in Step B and substituting(4-formyl-2-methylphenyl)boronic acid for3-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde inStep C.

Example 77: Synthesis of2-(2,2′-diethyl-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol

The aldehyde intermediate2,2′-diethyl-4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1′-biphenyl]-4-carbaldehydewas prepared using the procedure described in Step C of Example C, butsubstituting 2-(4-bromo-3-ethylphenyl)-1,1,1,3,3,3-hexafluoropropan-2-olfor Intermediate 1 and substituting3-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde forcompound 9.

The title compound was prepared using the general procedure using thealdehyde from the previous step and Amine Intermediate 2 from Example Q.

Example 78: Synthesis of1,1,1,3,3,3-hexafluoro-2-(5′-fluoro-2′-isopropyl-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)propan-2-ol

Step A. To a mixture of 2-fluoro-4-hydroxybenzoic acid (1.0 equiv),triethylamine (3.0 equiv) and N,O-dimethylhydroxylamine hydrochloride(10.0 equiv) in DMF (10 mL) was added HBTU (2.5 equiv). The mixture wasstirred at room temperature overnight. The reaction mixture was dilutedwith 40 mL EtOAc and 20 mL hexane and washed with 2N HCl, water, andbrine. The organic phase was dried over MgSO₄, concentrated, andpurified on a silica gel column to afford2-fluoro-4-hydroxy-N-methoxy-N-methylbenzamide.

Step B. To a solution of 2-fluoro-4-hydroxy-N-methoxy-N-methylbenzamide(1.0 equiv) in AcOH (10 mL) was added NBS (1.0 g) at 0° C. The reactionmixture was stirred at 0° C. to rt for 1 h, diluted with EtOAc, andwashed with water. The organic layer was concentrated and purified on asilica gel column to give5-bromo-2-fluoro-4-hydroxy-N-methoxy-N-methylbenzamide.

Step C. 5-Bromo-2-fluoro-4-hydroxy-N-methoxy-N-methylbenzamide wasdissolved in DMF, to which was added K₂CO₃ (3.0 equiv) and benzylbromide (1.2 equiv). The resulting mixture was heated at 50° C. for 1 h.The reaction was diluted with ethyl acetate and washed with water. Thecrude mixture was purified on a silica gel column to afford4-(benzyloxy)-5-bromo-2-fluoro-N-methoxy-N-methylbenzamide.

Step D. Standard Suzuki coupling between4-(benzyloxy)-5-bromo-2-fluoro-N-methoxy-N-methylbenzamide and4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane afforded4-(benzyloxy)-2-fluoro-N-methoxy-N-methyl-5-(prop-1-en-2-yl)benzamide.

Step E.4-(Benzyloxy)-2-fluoro-N-methoxy-N-methyl-5-(prop-1-en-2-yl)benzamide inMeOH was hydrogenated at 50 PSI in presence of Pd/C (10% by weight) for5 h to afford2-fluoro-4-hydroxy-5-isopropyl-N-methoxy-N-methylbenzamide.

Step F. To a mixture of2-fluoro-4-hydroxy-5-isopropyl-N-methoxy-N-methylbenzamide (1.0 equiv)and pyridine (3.0 equiv) in DCM (10 mL) was addedtrifluoromethanesulfonic anhydride (1.5 equiv) dropwise at 0° C. Themixture was stirred at 0° C. for 1 h, and washed with saturated NaHCO₃solution and water. The organic phase was dried over MgSO₄,concentrated, and purified on a silica gel column to afford5-fluoro-2-isopropyl-4-(methoxy(methyl)carbamoyl)phenyltrifluoromethanesulfonate as a white solid.

Step G. To a solution of5-fluoro-2-isopropyl-4-(methoxy(methyl)carbamoyl)phenyltrifluoromethanesulfonate (1.0 equiv) in anhydrous 1,4-dioxane (2 mL)was added boronic ester Intermediate 2 (1.3 equiv), 2M potassiumcarbonate solution (3.0 equiv), and Pd(PPh₃)₄ (0.05 equiv). The mixturewas bubbled N₂ for 5 min, and then stirred at 90° C. in a sealed tubefor 3 h. Upon cooling to room temperature, the mixture was poured intoNH₄Cl solution and extracted with DCM. The organic phase was dried overMgSO₄, concentrated, and purified on a silica gel column to afford5-fluoro-4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2-isopropyl-N-methoxy-N-methyl-[1,1′-biphenyl]-4-carboxamideas a white solid.

Step H. To a solution of5-fluoro-4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2-isopropyl-N-methoxy-N-methyl-[1,1′-biphenyl]-4-carboxamide(1 equiv) in anhydrous THF (2 mL) was added 1.0 M LAH solution in THF(1.0 equiv) at −78° C. The reaction was stirred at −78° C. for 1 h andquenched by adding EtOAc before being warmed to room temperature. Themixture was poured into NH₄Cl solution and extracted with DCM. Theorganic phase was dried over MgSO₄, concentrated, and purified on asilica gel column to afford5-fluoro-4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2-isopropyl-[1,1′-biphenyl]-4-carbaldehydeas a white solid.

Step I. The title compound was prepared using the general procedureusing the aldehyde intermediate from the previous step and AmineIntermediate 2.

Example 79: Synthesis of1,1,1,3,3,3-hexafluoro-2-(5′-fluoro-2′-isopropyl-2-methyl-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)propan-2-ol

The title compound was made using the procedure described in Example 78,but substituting Intermediate 2A for Intermediate 2 in Step G.

Example 80: Synthesis of2-(2,5′-difluoro-2′-isopropyl-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol

The title compound was made using the procedure described in Example 78,but substituting Intermediate 2C for Intermediate 2 in Step G.

Example 81: Synthesis of2-(2-chloro-5′-fluoro-2′-isopropyl-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol

The title compound was made using the procedure described in Example 78,but substituting Intermediate 2D for Intermediate 2 in Step G.

Example 82: Synthesis of2-(2′-ethyl-2,5′-difluoro-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol

The title compound was synthesized using the procedures described inSteps D through I of Example 78, but substituting4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane for4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane andsubstituting Intermediate 2C for Intermediate 2 in Step G.

Example 83: Synthesis of2-(2-chloro-2′-ethyl-5′-fluoro-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol

The title compound was synthesized using the procedures described inSteps D through I of Example 78, but substituting4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane for4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane andsubstituting Intermediate 2D for Intermediate 2 in Step G.

Example 84: Synthesis of2-(3′,6′-difluoro-2′-isopropyl-2-methyl-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol

The aldehyde intermediate3,6-difluoro-4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2-isopropyl-2′-methyl-[1,1′-biphenyl]-4-carbaldehydewas prepared using the procedure described in Example H, butsubstituting1,1,1,3,3,3-hexafluoro-2-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-olfor1,1,1,3,3,3-hexafluoro-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-olin Step F.

The title compound was prepared using the general procedure using thealdehyde intermediate from the previous step and Amine Intermediate 2.

Example 85: Synthesis of2-(2-ethyl-3′,6′-difluoro-2′-isopropyl-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol

The aldehyde intermediate2′-ethyl-3,6-difluoro-4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2-isopropyl-[1,1′-biphenyl]-4-carbaldehydewas prepared using the procedure described in Example H, butsubstituting2-(3-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-olfor1,1,1,3,3,3-hexafluoro-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-olin Step F.

The title compound was prepared using the general procedure using thealdehyde intermediate from the previous step and Amine Intermediate 2.

Example 86: Synthesis of1,1,1,3,3,3-hexafluoro-2-(2,3′,6′-trifluoro-2′-isopropyl-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)propan-2-ol

The aldehyde intermediate2′,3,6-trifluoro-4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2-isopropyl-[1,1′-biphenyl]-4-carbaldehydewas prepared using the procedure described in Example H, butsubstituting1,1,1,3,3,3-hexafluoro-2-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-olfor1,1,1,3,3,3-hexafluoro-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-olin Step F.

The title compound was prepared using the general procedure using thealdehyde intermediate from the previous step and Amine Intermediate 2.

Example 87: Synthesis of2-(2-chloro-3′,6′-difluoro-2′-isopropyl-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol

The aldehyde intermediate2′-chloro-3,6-difluoro-4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2-isopropyl-[1,1′-biphenyl]-4-carbaldehydewas prepared using the procedure described in Example H, butsubstituting2-(3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-olfor1,1,1,3,3,3-hexafluoro-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-olin Step F.

The title compound was prepared using the general procedure using thealdehyde intermediate from the previous step and Amine Intermediate 2.

Example 88: Synthesis of2-(2′-cyclopropyl-3′,6′-difluoro-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol

Step A. 2,5-difluoro-4-methoxybenzoic acid (500 mg) was treated withBBr₃ at room temperature for 24 h. The reaction was worked up with 2NHCl, and purified on a silica gel column to give the corresponding2,5-difluoro-4-hydroxybenzoic acid.

Step B. To a mixture of 2,5-difluoro-4-hydroxybenzoic acid (380 mg, 2.18mmol, 1.0 equiv), triethylamine (660 mg, 6.6 mmol, 3.0 equiv) andN,O-dimethylhydroxylamine hydrochloride (2.14 g, 21.8 mmol, 10.0 equiv)in DCM (20 mL) was added HBTU (1.25 g, 3.27 mmol, 1.5 equiv). Themixture was stirred at room temperature overnight. The mixture waswashed with saturated NaHCO₃ solution, 2N HCl, and water. The organicphase was dried over MgSO₄, concentrated, and purified on a silica gelcolumn to afford 2,5-difluoro-4-hydroxy-N-methoxy-N-methylbenzamide (190mg) as a colorless oil.

Step C. To a solution of2,5-difluoro-4-hydroxy-N-methoxy-N-methylbenzamide (190 mg, 0.87 mmol,1.0 equiv) in acetic acid (4 mL) was added NBS (190 mg, 1.05 mmol, 1.2equiv) at 0° C. The reaction was warmed to room temperature and stirredfor 2 h. The solvent was removed under reduced pressure. The residue wasdissolved in EtOAc, washed with water, concentrated, and purified on asilica gel column to afford3-bromo-2,5-difluoro-4-hydroxy-N-methoxy-N-methylbenzamide (240 mg) as awhite solid.

Step D. 3-Bromo-2,5-difluoro-4-hydroxy-N-methoxy-N-methylbenzamide (1.0equiv) and potassium cyclopropyltrifluoroborate (2.5 equiv) werecombined in dioxane (5 mL) and water (2 mL), then added K₂CO₃ (3.0equiv) and Pd(PPh₃)₄ (0.08 equiv). The resulting mixture was bubbled N₂for 5 min, then heated at 90° C. in sealed tube for 14 h. The reactionmixture was diluted with ethyl acetate and washed with saturated NH₄Cland water. The crude mixture was purified on a silica gel column toprovide3-cyclopropyl-2,5-difluoro-4-hydroxy-N-methoxy-N-methylbenzamide.

Step E. 3-Cyclopropyl-2,5-difluoro-4-hydroxy-N-methoxy-N-methylbenzamidewas treated with trifluoromethanesulfonic anhydride (1.5 equiv) inpresence of pyridine (1.5 equiv) as base at 0° C. to afford2-cyclopropyl-3,6-difluoro-4-(methoxy(methyl)carbamoyl)phenyltrifluoromethanesulfonate.

Step F. Suzuki coupling between2-cyclopropyl-3,6-difluoro-4-(methoxy(methyl)carbamoyl)phenyltrifluoromethanesulfonate and Intermediate 2 under conditions describedin Step A of Example K except with heating to 90° C. overnight, afforded2-cyclopropyl-3,6-difluoro-4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-N-methoxy-N-methyl-[1,1′-biphenyl]-4-carboxamide.

Step G.2-Cyclopropyl-3,6-difluoro-4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-N-methoxy-N-methyl-[1,1′-biphenyl]-4-carboxamidefrom the previous step was reduced to the aldehyde intermediate2-cyclopropyl-3,6-difluoro-4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1′-biphenyl]-4-carbaldehydeby LAH at −78° C.

Step H. The title compound was prepared using the general procedureusing the aldehyde intermediate from the previous step and AmineIntermediate 2.

Example 89: Synthesis of2-(2′-cyclopropyl-3′,6′-difluoro-2-methyl-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol

The title compound was made using the procedure described in Example 88,but substituting Intermediate 2A for Intermediate 2 in Step F.

Example 90: Synthesis of2-(2′-cyclopropyl-2-ethyl-3′,6′-difluoro-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol

The title compound was made using the procedure described in Example 88,but substituting Intermediate 2B for Intermediate 2 in Step F.

Example 91: Synthesis of2-(2′-cyclopropyl-2,3′,6′-trifluoro-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol

The title compound was made using the procedure described in Example 88,but substituting Intermediate 2C for Intermediate 2 in Step F.

Example 92: Synthesis of2-(2-chloro-2′-cyclopropyl-3′,6′-difluoro-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol

The title compound was made using the procedure described in Example 88,but substituting Intermediate 2D for Intermediate 2 in Step F.

Example 93: Gal4 Ligand Binding Assay

Compounds of the present invention were tested in a human RORγ ligandbinding assay using a commercially available cell based ligand bindingreporter assay in 96-well format (Cat # IB04001, INDIGO Biosciences,State College, Pa.). The N-terminal DNA binding domains (DBD) of thenative RORγ and RORγt receptors have been substituted with that of theyeast GAL4-DBD and stably transfected in HEK293T cells that also stablyexpress luciferase under the regulation by upstream activation sequenceof yeast Gal4. These cells constitutively express high level RORγactivity due to binding of endogenous co-factors. Both agonist andinverse agonist activity can be detected. The assay was performedaccording to kit manufacturer's instructions as follows. 10 mM compoundstocks were diluted serially 1:3 with DMSO and further diluted withprovided media to generate 10 titration points from 60 μM to 3 nM. Thesetreatment conditions were added to the plates as 2× media in 100 μLvolume. Each plate includes a positive control with 10 titration pointsas well as 6 negative control wells with vehicle only, with final DMSOconcentration of 0.2%. RORγ reporter cells were rapidly thawed and addedto the plates in 100 μL volume. The plates were incubated for 24 h in a37° C. humidified 5% CO₂ incubator. Media was removed before theaddition of room temperature luciferous detection substrate. After 5minute incubation, relative light units (RLUs) were quantified using aplate reading luminometer. Data was normalized to positive control wellswith only 0.2% o DMSO. Before establishing internal controls, ursolicacid was used as control.

TABLE 2 IC₅₀ values for RORγt inverse agonists in RORγt Gal fusionassay. Example RORγt No. (IC₅₀) 1 B 2 A 3 A 4 A 5 A 6 B 7 A 8 A 9 B 10 A11 A 12 B 13 A 14 A 15 A 16 A 17 B 18 A 19 B 20 B 21 B 22 B 23 A 24 B 25C 26 B 27 B 28 C 29 C 30 A 31 A 32 C 33 B 34 A 35 A 36 A 37 A 38 B 39 A40 B 41 B 42 A 43 A 44 A 45 B 46 B 47 C 48 C 49 C 50 B 51 C 52 B 53 B 54B 55 C 56 B 57 A 58 A 59 B 60 A 61 B 62 B 63 B 64 A 65 A 66 B 67 C 68 A69 A 70 A 71 A 72 A 73 C 74 B 75 A 76 A 77 A 78 A 79 A 80 A 81 A 82 A 83A 84 A 85 A 86 A 87 A 88 A 89 A 90 A 91 A 92 A A: IC₅₀ < 50 nM; B: IC₅₀= 50 nM-250 nM; C: IC₅₀ > 250 nM

Example 94: Human PBMC T_(H)17 Differentiation Assay

This assay tests compounds for their modulatory effect on RORγt asmeasured by IL-17 production by CD4+ T cells under conditions whichfavor T_(H)17 differentiation. Fresh healthy donor peripheral bloodmononuclear cells (PBMC) were isolated using a Ficoll gradient. CD4+ Tcells were purified using a negative selection kit and magneticseparation from Stemcell Technologies according to manufacturer'sinstruction (Cat #17952, Vancouver, Canada). 2.5×10⁴ CD4+ T cells wereincubated per well in a 96-well plate with 1:1 ratio of anti-CD3/CD28stimulation beads (Cat #11131D, Gibco DYNAL, Waltham, Mass.) in thepresence of rhIL-6 (50 ng/mL), rhIL-1b (10 ng/mL), rhTGF-b1 (1 ng/mL),rhIL-23 (5 ng/mL), anti-IL-4 (10 ug/mL) and anti-IFNg (10 ug/mL).Compounds were added 1 h before the start of the differentiation atvarious concentrations, with a final concentration of 0.1% DMSO. Cellswere incubated at 37° C. 5% CO₂ for 3 days before harvesting of thesupernatant for U-plex human IL-17A ELISA (Cat # K151ATA-4, Meso ScaleDiscovery, Rockville, Md.). Data was normalized to DMSO control wells.Cell viability was also measured after the supernatant removal, usingMTT assay kit (CAT #11465007001, Sigma-Aldrich, St. Louis, Mo.).

In one embodiment, the compounds provided herein were found to haveIC₅₀s of less than about 500 nM. In another embodiment, the compoundsprovided herein were found to have IC₅₀s of less than about 250 nM. Inanother embodiment, the compounds provided herein were found to haveIC₅₀s of less than about 200 nM. In another embodiment, the compoundsprovided herein were found to have IC₅₀s of less than about 150 nM. Inanother embodiment, the compounds provided herein were found to haveIC₅₀s of less than about 100 nM.

Example 95: Patient PBMC IL-17A Inhibition Assay

This assay is designed to screen compounds for their inhibitory effecton the release of IL-17 from isolated human TH17 cells. Peripheral bloodmononuclear cells (PBMC) from psoriasis, systemic lupus erythematosus,Crohn's disease and rheumatoid arthritis patients were purchased fromPrecision For Medicine (Frederick, Md.). 4×10⁵ cells were incubated perwell in a 96-well plate with Cytostim, human (Cat #130-092-172, MiltenyiBiotec, Bergisch Gladbach, Germany) according to manufacturer'sinstructions. Cells were incubated in the presence or absence of variousconcentrations of compounds, with a final concentration of 0.1% DMSO andstarting at the time of stimulation. After 48 hours of incubation at 37°C. and 5% CO₂, supernatant was removed to measure IL-17A by ELISA (Cat #BMS2017, ThermoFisher Scientific, Waltham, Mass.). Data was normalizedto DMSO control wells. Cell viability was also measured after thesupernatant removal, using CellTiter-Glo Luminescent Cell ViabilityAssay Kit (Cat # G7570, Promega, Madison, Wis.).

In one embodiment, the compounds provided herein were found to haveIC₅₀s of less than about 5 μM. In one embodiment, the compounds providedherein were found to have IC₅₀s of less than about 2.5 μM. In oneembodiment, the compounds provided herein were found to have IC₅₀s ofless than about 2 μM. In one embodiment, the compounds provided hereinwere found to have IC₅₀s of less than about 1 μM. In another embodiment,the compounds provided herein were found to have IC₅₀s of less thanabout 1500 nM. In another embodiment, the compounds provided herein werefound to have IC₅₀s of less than about 500 nM. In another embodiment,the compounds provided herein were found to have IC₅₀s of less thanabout 250 nM. In another embodiment, the compounds provided herein werefound to have IC₅₀s of less than about 300 nM. In another embodiment,the compounds provided herein were found to have IC₅₀s of less thanabout 200 nM. In another embodiment, the compounds provided herein werefound to have IC₅₀s of less than about 150 nM. In another embodiment,the compounds provided herein were found to have IC₅₀s of less thanabout 100 nM. In another embodiment, the compounds provided herein werefound to have IC₅₀s of less than about 50 nM.

The examples and embodiments described herein are for illustrativepurposes only and in some embodiments, various modifications or changesare to be included within the purview of disclosure and scope of theappended claims.

What is claimed is:
 1. A compound having the Formula (I):

or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein:

is phenyl, or a 5-membered or 6-membered heteroaryl ring;

is phenyl, or a 5-membered or 6-membered heteroaryl ring; Z is—(C(R⁶)(R⁷))_(t)—; R¹ and R² are selected from (i) and (ii): (i) R¹ andR², together with the carbon atom to which they are attached, form a 4-,5-, or 6-membered heterocyclyl ring wherein the 4-, 5-, or 6-memberedheterocyclyl ring is optionally substituted with 1 to 4 R^(3a) groups;and (ii) R¹ is hydrogen and R² is —S(O)₂R¹⁰, —C₁-C₆alkyl-S(O)₂R¹⁰,—N(R¹¹)S(O)₂R¹⁰, or —C₁-C₆alkyl-N(R¹¹)S(O)₂R¹⁰; each R³ is independentlyselected from halo and C₁-C₆alkyl; each R^(3a) is independently selectedfrom C₁-C₆alkyl, C₁-C₆haloalkyl, C₂-C₉heteroaryl,(C₂-C₉heteroaryl)-C₁-C₆alkylene-, oxo, —S(O)₂R¹⁰, —C(O)R¹⁰, —C(O)OR¹¹,and —C(O)N(R¹)₂, wherein C₂-C₉heteroaryl and(C₂-C₉heteroaryl)-C₁-C₆alkylene- are optionally substituted with 1 to 3groups independently selected from halo, C₁-C₆alkyl, C₁-C₆haloalkyl, andhydroxyl; each R⁴ and each R⁵ are each independently selected from halo,cyano, —OH, C₁-C₆alkyl, C₁-C₆alkenyl, C₁-C₆haloalkyl, C₁-C₆alkoxy,C₃-C₈cycloalkyl, —N(R⁹)₂, —C(O)R⁸, —C(O)OR⁹, —C(O)N(R⁹)₂, —N(R⁹)C(O)R⁸,—N(R⁹)SO₂R⁸, —SO₂R⁸, and —SO₂N(R⁸)₂; each R⁶ and each R⁷ are eachindependently hydrogen, halo, or C₁-C₆alkyl; each R⁸ is independentlyC₁-C₆alkyl or C₁-C₆haloalkyl; each R⁹ is independently hydrogen,C₁-C₆alkyl, or C₁-C₆haloalkyl; each R¹⁰ is independently C₁-C₆alkyl,C₁-C₆haloalkyl, C₁-C₆alkyl-O—C₁-C₆alkyl-, C₃-C₈cycloalkyl,C₂-C₉heterocyclyl, phenyl, (phenyl)-C₁-C₆alkylene-, C₂-C₉heteroaryl, or(C₂-C₉heteroaryl)-C₁-C₆alkylene-, wherein the C₃-C₈cycloalkyl,C₂-C₉heterocyclyl, phenyl, (phenyl)-C₁-C₆alkylene-, C₂-C₉heteroaryl, or(C₂-C₉heteroaryl)-C₁-C₆alkylene- is optionally substituted with 1 to 3groups selected from halo, C₁-C₆alkyl, C₁-C₆haloalkyl, and hydroxyl;each R¹¹ is independently hydrogen, C₁-C₆alkyl, or C₁-C₆haloalkyl; m is1, 2, or 3; n is 1, 2, or 3; k is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, or4; q is 0, 1, 2, 3 or 4; and t is 0, 1, 2, or
 3. 2. The compound ofclaim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, wherein

is phenyl or a 6-membered heteroaryl ring.
 3. The compound of claim 1 or2, or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, wherein

is phenyl.
 4. The compound of claim 1 or 2, or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein

is a 6-membered heteroaryl ring.
 5. The compound of claim 4, or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein

is pyridyl.
 6. The compound of any one of claims 1-5, or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein

is phenyl or a 6-membered heteroaryl ring.
 7. The compound of any one ofclaims 1-6, or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein

is phenyl.
 8. The compound of any one of claims 1-6, or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein

is a 6-membered heteroaryl ring.
 9. The compound of claim 8, or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein

is pyridyl.
 10. The compound of any one of claims 1-9, or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein R¹ and R², together with the carbon atom to which they areattached, form a 4-, 5-, or 6-membered heterocyclyl ring wherein the 4-,5-, or 6-membered heterocyclyl ring is optionally substituted with 1 to4 R^(3a) groups.
 11. The compound of any one of claims 1-10, or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein R¹ and R², together with the carbon atom to which they areattached, form a 4-, 5-, or 6-membered heterocyclyl ring wherein the 4-,5-, or 6-membered heterocyclyl ring is optionally substituted with 1 to2 R^(3a) groups.
 12. The compound of claim 11 having the Formula (II),or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:

wherein: X is —O—, —NH—, —N(R^(3a))—, —S—, —S(O)—, or —S(O)₂—; a is 1 or2; and b is 1 or 2;
 13. The compound of claim 12, or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein a is 1, b is1, m is 2, and n is
 2. 14. The compound of claim 12, or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein a is 1, b is 2, m is 1, and n is
 2. 15. The compound of claim12, or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, wherein a is 1, b is 1, m is 1, and n is
 2. 16. The compound ofclaim 12, or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein a is 2, b is 2, m is 1, and n is
 1. 17.The compound of claim 12, or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein a is 2, b is 1, m is 1, and nis
 1. 18. The compound of claim 12, or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, wherein a is 1, b is 1, m is 1,and n is
 1. 19. The compound of claim 12 having the Formula (IIa):

or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.20. The compound of any one of claims 1-19, or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein R^(3a) is—S(O)₂R¹⁰, —C(O)R¹⁰, or —C(O)OR¹¹.
 21. The compound of any one of claims1-20, or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, wherein R^(3a) is —S(O)₂R¹⁰.
 22. The compound of any one ofclaims 1-21, or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein R¹⁰ is C₁-C₆alkyl or C₃-C₈cycloalkyl. 23.The compound of any one of claims 1-22, or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, wherein R¹⁰ is C₁-C₆alkyl. 24.The compound of any one of claims 1-23, or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, wherein R^(3a) is —S(O)₂CH₃. 25.The compound of any one of claims 1-9, or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, wherein R¹ is hydrogen and R² is—S(O)₂R¹⁰, —C₁-C₆alkyl-S(O)₂R¹⁰, —N(R¹¹)S(O)₂R¹⁰, or—C₁-C₆alkyl-N(R¹¹)S(O)₂R¹⁰.
 26. The compound of claim 25, or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein R² is —S(O)₂R¹⁰, —CH₂S(O)₂R¹⁰, —N(R¹¹)S(O)₂R¹⁰, or—CH₂N(R¹¹)S(O)₂R¹⁰.
 27. The compound of claim 26, or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein R¹⁰ isC₁-C₆alkyl.
 28. The compound of claim 27, or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein R² is—S(O)₂CH₃, —CH₂S(O)₂CH₃, —CH₂N(H)S(O)₂CH₃, or —CH₂N(CH₃)S(O)₂CH₃. 29.The compound of any one of claims 25-28, or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein m is 1 and nis
 1. 30. The compound of any one of claims 25-28, or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein m is 2 and nis
 1. 31. The compound of any one of claims 25-28, or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein m is 2 and nis
 2. 32. The compound of any one of claims 1-31, or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein each R⁶ andeach R⁷ are hydrogen.
 33. The compound of any one of claims 1-32, or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein t is 1, 2, or
 3. 34. The compound of any one of claims 1-33, ora pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein t is
 1. 35. The compound of any one of claims 1-34, or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein p is 0, 1, 2, or
 3. 36. The compound of any one of claims 1-35,or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein each R⁴ is independently halo, C₁-C₆alkyl, C₁-C₆alkenyl,C₁-C₆haloalkyl, C₁-C₆alkoxy, or C₃-C₈cycloalkyl.
 37. The compound of anyone of claims 1-36, or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein each R⁴ is independently halo, C₁-C₆alkyl,or C₃-C₈cycloalkyl.
 38. The compound of any one of claims 1-37, or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein p is
 1. 39. The compound of any one of claims 1-37, or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein p is
 2. 40. The compound of any one of claims 1-37, or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein p is
 3. 41. The compound of any one of claims 1-35, or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein p is
 0. 42. The compound of any one of claims 1-41, or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein q is 0, 1, or
 2. 43. The compound of any one of claims 1-42, ora pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein each R⁵ is independently halo, cyano, C₁-C₆alkyl,C₁-C₆haloalkyl, or C₁-C₆alkoxy.
 44. The compound of any one of claims1-43, or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, wherein each R⁵ is independently halo or C₁-C₆alkyl.
 45. Thecompound of any one of claims 1-44, or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, wherein q is
 1. 46. The compoundof any one of claims 1-42, or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein q is
 0. 47. The compound ofany one of claims 1-46, or a pharmaceutically acceptable salt, solvate,or stereoisomer thereof, wherein k is
 0. 48. The compound of claim 1, ora pharmaceutically acceptable salt or solvate thereof, selected from:2-(2′-ethyl-4′-((4-((methylsulfonyl)methyl)piperidin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;2-(2′-ethyl-4′-((4-(methylsulfonyl)piperidin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;N-((1-((2-ethyl-4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1′-biphenyl]-4-yl)methyl)azetidin-3-yl)methyl)-N-methylmethanesulfonamide;andN-((1-((2-ethyl-4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1′-biphenyl]-4-yl)methyl)azetidin-3-yl)methyl)methanesulfonamide.49. The compound of claim 1, or a pharmaceutically acceptable salt orsolvate thereof, selected from:2-(3′,6′-difluoro-2′-isopropyl-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;2-(3′,5′-difluoro-2′-isopropyl-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;6-((4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2-isopropyl-2′-methyl-[1,1′-biphenyl]-4-yl)methyl)-2-thia-6-azaspiro[3.4]octane2,2-dioxide;6-((4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2-isopropyl-2′-methyl-[1,1′-biphenyl]-4-yl)methyl)-2-thia-6-azaspiro[3.3]heptane2,2-dioxide;2-(2′-ethyl-4′-((6-(methylsulfonyl)-2-azaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;2-(2′-(sec-butyl)-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;2-(2′,3′-difluoro-6′-isopropyl-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;1,1,1,3,3,3-hexafluoro-2-(2′-fluoro-6′-isopropyl-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)propan-2-ol;6-((2-ethyl-4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2′-methyl-[1,1′-biphenyl]-4-yl)methyl)-2-thia-6-azaspiro[3.4]octane2,2-dioxide;6-((2-ethyl-4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1′-biphenyl]-4-yl)methyl)-2-thia-6-azaspiro[3.4]octane2,2-dioxide;6-((2-ethyl-4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2′-methyl-[1,1′-biphenyl]-4-yl)methyl)-2-thia-6-azaspiro[3.3]heptane2,2-dioxide;2-(2′-ethyl-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.5]nonan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;2-(2′-ethyl-4′-((2-(methylsulfonyl)-2,6-diazaspiro[3.5]nonan-6-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;2-(2′-ethyl-4′-((6-(isobutylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;2-(2′-ethyl-4′-((6-(propylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;2-(2′-ethyl-4′-((6-(ethylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;2-((2-ethyl-4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1′-biphenyl]-4-yl)methyl)-7-thia-2-azaspiro[3.5]nonane7,7-dioxide;2-(2′-(tert-butyl)-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;2-((2-ethyl-4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1′-biphenyl]-4-yl)methyl)-6-thia-2-azaspiro[3.4]octane6,6-dioxide;2-((2-ethyl-4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1′-biphenyl]-4-yl)methyl)-6-thia-2-azaspiro[3.4]octane6-oxide;6-((2-ethyl-4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1′-biphenyl]-4-yl)methyl)-2-thia-6-azaspiro[3.3]heptane2,2-dioxide;6-((2-ethyl-4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1′-biphenyl]-4-yl)methyl)-2-thia-6-azaspiro[3.3]heptane2-oxide;2-(4′-((2-thia-6-azaspiro[3.3]heptan-6-yl)methyl)-2′-ethyl-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;2-(2′-ethyl-4′-((2-(methylsulfonyl)-2,6-diazaspiro[3.4]octan-6-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;2-(2′-ethyl-4′-((7-(methylsulfonyl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;2-(2′-ethyl-4′-((7-(methylsulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;2-(2′-ethyl-4′-((2-(methylsulfonyl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;2-(2′-ethyl-2-fluoro-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;2-(2′-ethyl-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.4]octan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;2-(2′-ethyl-6′-fluoro-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;2-(2′-ethyl-5′-fluoro-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;2-(2′-ethyl-3′-fluoro-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;tert-butyl2-((2-ethyl-4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1′-biphenyl]-4-yl)methyl)-2,6-diazaspiro[3.4]octane-6-carboxylate;2-(2′-ethyl-2-methyl-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;methyl6-((2-ethyl-4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1′-biphenyl]-4-yl)methyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate;2-(4′-((6-(cyclopropylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-2′-ethyl-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;2-(2′-cyclopropyl-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;1,1,1,3,3,3-hexafluoro-2-(2′-isopropyl-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)propan-2-ol;tert-butyl6-((2-ethyl-4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1′-biphenyl]-4-yl)methyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate;1,1,1,3,3,3-hexafluoro-2-(4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-2′-(prop-1-en-2-yl)-[1,1′-biphenyl]-4-yl)propan-2-ol;2-(2′-bromo-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;1,1,1,3,3,3-hexafluoro-2-(4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-2′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)propan-2-ol;2-(2′-chloro-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;1-(6-((2-ethyl-4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1′-biphenyl]-4-yl)methyl)-2,6-diazaspiro[3.3]heptan-2-yl)ethan-1-one;2-(2′-ethyl-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;1-(6-((4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2-methyl-[1,1′-biphenyl]-4-yl)methyl)-2,6-diazaspiro[3.3]heptan-2-yl)ethan-1-one;1,1,1,3,3,3-hexafluoro-2-(2′-methyl-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)propan-2-ol;1,1,1,3,3,3-hexafluoro-2-(2′-methyl-4′-((6-(pyridin-4-ylmethyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)propan-2-ol;2-(4-(3-ethyl-5-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)pyridin-2-yl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol;7-((2-ethyl-4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1′-biphenyl]-4-yl)methyl)-2,7-diazaspiro[4.4]nonan-1-one;7-((2-ethyl-4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1′-biphenyl]-4-yl)methyl)-2,7-diazaspiro[4.4]nonan-3-one;4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-N,N-dimethyl-4-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-2-carboxamide;2-(2′-ethyl-2-methoxy-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;1,1,1,3,3,3-hexafluoro-2-(2′-methoxy-2-methyl-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)propan-2-ol;7-((2-ethyl-4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1′-biphenyl]-4-yl)methyl)-2-thia-7-azaspiro[4.4]nonane2,2-dioxide;2-(5-(2-ethyl-4-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)phenyl)pyridin-2-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;2-(4-(4-ethyl-6-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)pyridin-3-yl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol;4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-4-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-3-ol;2-(2′-cyclopropyl-3′,6′-difluoro-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;2-(2′-cyclopropyl-2,3′,6′-trifluoro-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;2-(2-chloro-2′-cyclopropyl-3′,6′-difluoro-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;1,1,1,3,3,3-hexafluoro-2-(2,3′,6′-trifluoro-2′-isopropyl-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)propan-2-ol;2-(2′-cyclopropyl-2-ethyl-3′,6′-difluoro-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;2-(2′-cyclopropyl-3′,6′-difluoro-2-methyl-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;2-(2-chloro-5′-fluoro-2′-isopropyl-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;1,1,1,3,3,3-hexafluoro-2-(5′-fluoro-2′-isopropyl-2-methyl-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)propan-2-ol;2-(2,5′-difluoro-2′-isopropyl-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;2-(2-chloro-3′,6′-difluoro-2′-isopropyl-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;2-(2-ethyl-3′,6′-difluoro-2′-isopropyl-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;2-(3′,6′-difluoro-2′-isopropyl-2-methyl-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;2-(2′-ethyl-3′,6′-difluoro-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;2-(2,2′-diethyl-3′,6′-difluoro-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;2-(2-chloro-2′-ethyl-3′,6′-difluoro-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;2-(2-chloro-2′-ethyl-5′-fluoro-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;2-(2′-ethyl-2,5′-difluoro-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;1,1,1,3,3,3-hexafluoro-2-(5′-fluoro-2′-isopropyl-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)propan-2-ol;2-(2,2′-diethyl-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;2-(2′-ethyl-2,3′,6′-trifluoro-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;2-(2-ethyl-2′-methyl-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;2-(2-chloro-2′-ethyl-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;2-(3′,6′-difluoro-2′-isopropyl-4′-((2-(methylsulfonyl)-2,6-diazaspiro[3.4]octan-6-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;2-(4-(2-ethyl-6-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)pyridin-3-yl)-3-methylphenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol;2-(2′-ethyl-3′,6′-difluoro-2-methyl-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;2′-ethyl-4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-4′-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1′-biphenyl]-2-carbonitrile;2-(4-(4-ethyl-6-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)pyridin-3-yl)-3-methylphenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol;2-(6-(2-ethyl-4-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)phenyl)pyridin-3-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;2-(4-(3-ethyl-5-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)pyridin-2-yl)-3-methylphenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol;1,1,1,3,3,3-hexafluoro-2-(3-methyl-4-(6-(6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)phenyl)propan-2-ol;and2-(2,2′-dimethyl-3′-(6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;or a pharmaceutically acceptable salt or solvate thereof.
 50. Apharmaceutical composition comprising a compound of any one of claims1-49, or a pharmaceutically acceptable salt or solvate thereof, and apharmaceutically acceptable carrier.
 51. A method of treating a disease,disorder or condition in an individual in need thereof comprisingadministering to the individual a therapeutically effective amount of acompound of any one of claims 1-49, or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, wherein the disease, disorder orcondition is selected from psoriasis, psoriatic arthritis, uveitis,ulcerative colitis, asthma, allergic rhinitis, chronic obstructivepulmonary disease (COPD), atopic dermatitis, vitiligo, vesiculobullousdermatosis, rheumatoid arthritis, ankylosing spondylitis, reactivearthritis, arthritis associated with inflammatory bowel disease,juvenile rheumatoid arthritis, Crohn's disease, inflammatory boweldisease, lupus, lupus nephritis, multiple sclerosis, axialspodyloarthritides, hidraenitis suppurativa, Sjögren's syndrome,regional enteritis, Tolosa-Hunt syndrome, undifferentiated connectivetissue disease, obesity, obesity-induced insulin resistance,atherosclerosis, and type II diabetes.